16beta-hydroxy-21-carboxylic acid gamma-lactones of the pregnane series and process for the preparation thereof



United States Patent 16/5 HYDRGXY 21 CARBQXYLEC AQID 'y LAC- TUNES @F THE PREGNANE SERKES AND PRUG ESE IFQR THE PREPARATION THEREOF Fiohn E. Pike, Kalamazoo, Mich, assignor to The Upjohn Qornpany, Kaiamazoo, Mich, a corporation of Delaware No Drawing. Filed May 16, 1962, Ser. No. 195,33?

41 Claims. (Cl. 260-23957) This invention relates to novel steroid 16,6-hydroxy-2lcarhoxylic acid 'y-lactones of the pregnane series having in ring D the structure wherein R is selected from the group consisting of hydrogen and methyl, and novel steroid intermediates and methods used in the preparation thereof.

More particularly, this invention relates to novel steroid 16,8-hydroxy-2l-carboxylic acid y-lactones represented by the following formulae:

(I) it A 3,152,631? Patented Dec. 22, 1964 O I ll n r 51 M05;

wherein the 1,2-carbon atom linkage is selected from the group consisting of single and double bond linkages, R is selected from the group consisting of hydrogen and the acyl radical of a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms, inclusive, W is selected from the group consisting of methylene CH ,B'hydroxymethylene carbonyl C:O), ot-hydroxymethylene OH a and a-acyloxymethylene R being the acyl radical of a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms, inclusive, and provided that R is the same as R when R is an acyl radical X is selected from the group consisting of B-hydroxymethylene OH H and carbonyl C O), Y is selected from the group consisting of methylene CH ,B-hydroxymethylene and carbonyl C=O), Z is selected from the group consisting of hydrogen and fluorine, X and Z and Y and Z can together constitute a 9(11)-double bond.

The novel compounds of Formula L and more particularly the compounds of Formulas 1, 2a, 2b, 2c, 3, 4a, 4b, 5a, 5b, 6, 7a and 7b possess useful therapeutic properties. Each possesses cardiotonic, anti-inflammatory, salt and water regulating, pituitary inhibiting, anti-anabolic, muscle relaxant antifertility, cytotoxic, anti=viral, and antimicrobial activities.

The compounds of the formulas depicted above are useful in the treatment of diseases of animals and are particularly useful in the treatment of inflammatory conditions of mammals and birds, such as the treatment of inflammatory conditions of the skin, eyes and ears of valuable domestic animals, as well as contact dermatitis and other allergic reactions.

Additionally, the compounds of the formulas depicted above are useful in treating mental disease states and circulatory diseases in mammals and birds, and more particularly in valuable domestic animals. These compounds have digitalis-like activity in increasing the contractility of the heart muscle, diminishing the heart rate and improving cardiac efiiciency. In addition, they possess the advantage of a greater margin of safety relative to digitalis and related drugs.

Administration of the compounds of Formulas L, 1, 2a, 2b, 2c, 3, 4a, 4b, 5a, 5b, 6, 7a and 7b can be in conventional dosage forms, such as pills, tablets, capsules, syrups or elixirs for oral use, or' in liquid forms which are suitable for injectable products. They can also be administered topically in the form of ointments, creams, lotions and the like, with or without coacting antibiotics, germicides or other materials forming advantageous combinations therewith.

The compounds of the formulae given above are also useful as ultraviolet screens. When used topically they absorb a portion of the erythema producing ultraviolet bands and at the same time permit the tanning ultraviolet bands to come through and are thus useful ultraviolet screening agents in the tanning of human skin.

The compounds of Formulas L, 1, 2a, 2b, 2c, 3, 4a, 4b, 5a, 5b, 6, 7a and 7b, in non-toxic solutions, are also useful for the irrigation of surgical wounds, particularly following the removal of tumorous tissues to prevent wound seeding.

The novel compounds of Formula L and more particularly the compounds of Formulas 1, 2a, 2b, 2c, 3, 4a,

4b, 5a, 5b, 6, 7a and 7b are produced according to the following reaction scheme:

/ Reaction C A R 1 Dehydrohalogenation III wherein Q is the remainder of the steroid moiety, R is selected from the group consisting of hydrogen and methyl and V is selected from the group consisting of iodine, bromine and chlorine.

In this application unless specifically designated as cis or trans, the carbomethoxy group attached to the double bonded (1-20 carbon atom of the compounds of Formula I includes both the cis and transconfiguration and/ or mixtures thereof. The compounds of Formula I having the cis configuration are the preferred starting materials since they are more readily available than those having the trans configuration.

The wavy line (I) appearing at the 16-position of Formula I is a generic expression inclusive of the a and ,B-configurations or mixtures thereof. The configuration at the l6-position of the starting material is immaterial since, as shown by the reaction scheme, the compounds of Formula Ii can have only one configuration due to the presence of the double bond at the 16-position, and the latter are in turn converted into compounds capable of having only the IGCC-COHfigUX'EtlOH as shown by Formulas 1H and IV.

The process of the present invention comprises treating the Faworskii esters, the compounds of Formula I, such as methyl 3,6-hydroxy-l1-keto-5a-pregn-17(20)-en- 21-0ate, with a base to obtain the compounds of Formula H, such as 3fi-hydroxy-11-keto-5a-pregn-16(l7)-en-21-oic acid. The conversion of the compounds of Formula I to the compounds of Formula Ii, Reaction A, involves the hydrolysis of the 21-ester group accompanied by a tautomeric shift of the l7(20)-double bond to the 16(17)- position.

The conversion of the compounds of Formula I to the compounds of Formula II is carried out according to rocedures well known in the art, such as those disclosed by Hogg et al., J. Amer. Chem. Soc. 77, 4436 (1955). Suitable bases are inorganic bases, for example, alkalimetal hydroxides, e.g., potassium hydroxide, sodium hydroxide, and the-like, alkali bicarbonates and carbonates, e.g., potassium bicarbonate, sodium bicarbonate, and the like, and lithium halides in organic solvents, for example, lithium iodide in piperidine, collidine and the like. Advantageously the reaction is carried out in an aqueous medium at temperatures of from 30 C. to 200 C. An inert reaction solvent, e.g., methanol, ethanol, dioxane, tetrahydrofuran, ethylene glycol, diethylene glycol, diglyme, and the like, can also be employed, particularly where the starting steriod is ditlieultly or moderately soluble in water.

Where the compounds of Formula II are available as starting materials, Reaction A of the process, namely, the hydrolysis of the 2l-ester group, accompanied by a tautomeric shift of the l7(20)-double bond to the 16(17)- position, is obviously eliminated as is shown in Example 3.

Reaction A, besides producing the compounds of Formula II, also produces in varying degrees, depending on the starting steriod, compounds represented by the following formula:

dn (IQ? wherein Q and R are defined as above. The Zl-tree acid compounds of Formula V upon recovery from the reaction mixture, as described below, are reesterified according to procedures well known in the art for the esterification of steroid free acid, such as those disclosed by Reindel and lliederlander, Ber. 68B, l96973 (1935), and the reesteriiied steriod is used as the starting steriod in Reaction A.

The compounds of Formula II and V are recovered following Reaction A by fractional crystallization, chromatography of the total crude alkaline hydrolysis reaction product on acid-washed alumina, Florisil (synthetic magnesium silicate), silica-gel, or silicic acid, eluting with chloroform containing increasing amounts of methanol or hexanes containing increasing amounts of acetone, Craig countercurrent partition separation, column partition chromatography, preparative paper chromatography, of a combination of these.

Alternatively, the entire reaction mixture obtained following Reaction A can be used in the subsequent halolactonization reaction, Reaction B, and the compounds of Formula V can be separated from the halolactone, the compounds of Formula 111.

Following recovery of the compounds of Formula V from Reaction B, they can be reesterified and recycled to Reaction A for use as starting materials.

Reaction B, the conversion of the compounds of Formula II, such as Zip-hydroxy-l1-keto5ot-pregn-l6(17)-en- Zl-oic acid, to the compounds of Formula Ill, such as 35,1613 dihydroxy ll-keto-l7a-iodo-5ot-pregnan-2l-oic acid y-lactone, is carried out by reacting the starting steroid of this step of the process (the compounds of Formula ll) with iodine. The iodolactonization reaction, Reaction B, is carried out in an alkaline aqueous medium and in the presence of an alkali metal or alkaline earth metal iodide, e.g., sodium or potassium iodide, calcium iodide, and the like, preferably potassium iodide. The alkaline medium is obtained by using relatively water soluble alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates, alkaline earth bicarbonates, alkali metal hydroxides, alkaline earth hydroxides, e.g., sodium or potassium carbonate, calcium carbonate, sodium or potassium bicarbonate, barium bicarbonate, sodium or potassium hydroxide, calcium hydroxide, and the like, preferably sodium and potassium carbonate.

While the halolactonization reaction, Reaction B, has been described with particularity, using iodine as the halogen, other halogens, bromine or chlorine, can be used to form the corresponding 17ot-b'romolactones and 17achlorolactones embraced by Formula Hi. When bromine or chlorine are used in the halolactonization step, the corresponding bromide or chloride is substituted for the various iodides given above.

The halolactonization reaction is carried out at temperatures of from about 30 to for about 1 to 24 hours.

The compounds of Formula Ill, such as 35,16,6-dihYClIOXY-l1-k6t0-17a-lOd0-5oc-PI6gIl3I1-2l-QiC acid 'y lactone, are recovered from the reaction mixture (Reaction B) using the methods described above for the recovery of the compounds of Formula ll from Reaction A.

The compounds of Formula V, if they have not previously been separated from the compounds of Formula 11 following Reaction A, can be separated from the compounds of Formula Ill following Reaction B by the methods described above for the separation of the compounds of Formula H from the compounds of Formula V, reesterified and recycled for use as starting materials.

Alternatively, the entire crude product obtained from Reaction B can be used in the subsequent dehydrohalogenation reaction, Reaction C, and the compounds of Formula V separated from the 16fl-hydroxy-2l-carboxylic acid -lactones, the compounds of Formula IV, in the manner described above for the separation of the compounds of Formula V from the compounds of Formula H. The compounds of Formula V separated from Reaction C, can be reesterified and recycled for use as starting materials.

As shown above, the compounds of Formula V can be recovered following steps A or B of the reaction scheme, or carried through the last step, Reaction C, reesterified and recycled as starting materials. Generally, it is preferred to separate the compounds of Formula V at the earliest time possible, namely, following Reaction A.

The compounds of Formula HI, such as 3fi,16;3-dihydroxy-ll-keto-17ot-iodo-5a-pregnan-2l-oic acid 7 lactone, are then dehydroiodinated (Reaction C) to give 3,8,165-dihydroxy-1 1-keto-5a-pregn-17(20)-en-21-oic acid 'y-lactone. The dehydroiodination is carried out by treating the iodolactone with a tertiary amine, e.g., pyridine, trimethylamine, triethylamine, collidine lutidine or by other methods known in the art to effect dehydrohalogenation, e.g., with lithium halides in dimethylformamide, diethylformamide and the like or with trimethyl phosphite or triethyl phosphite and the like. In the preferred method, the dehydroiodination is effected with pyridine, followed by separation of the product, for example, 3 8, l6fl-dihydroxy-l l-keto-5a-pregn-l7(2())-en-21-oic acid lactone, using the known methods described above.

The dehydroiodination reaction can be carried out at temperatures ranging from 30 to 200, with room temperature being preferred, for from 1 to 72 hours.

While the dehydrohalogenation (Reaction C) has been described with particularity using an iodolactone, other halolactones, i.e., chlorolactones and bromolactones, can also be used.

The compounds of Formula W containing acylatable hydroxyl groups can be acylated according to procedures known in the art, for example, those disclosed in U.S. Patent 2,877,241. Suitable acylating agents are organic carboxylic acids, particularly hydrocarbon carboxylic acids, containing from 1 to 12 carbon atoms, inclusive, or the anhydrides or acid halides thereof, for example, a saturated straight-chain aliphatic acid, e.g., formic, acetic, propionic, butyric, valeric, hexanoic, lauric, a saturated branched-chain aliphatic acid, e.g., trimethylacetic, isobutyric, isovaleric, tertiary butylacetic, a cycloaliphatic saturated acid, e.g., [B-cyclopentylpropionic, cyclohexanecarboxylic, cyclohexylacetic, an alkaryl acid, e.g., benzoic, phenylacetic, p-phenylpropionic, o-, m, p-toluic, a saturated dibasic acid (which can be converted into water-soluble, e.g., sodium, salts), e.g., succinic, adipic, a mono-basic unsaturated acid, e.g., acrylic, crotonic, undecylenic, propiolic, undecolic, cinnarnic, dibasic unsaturated acids (which can be converted into water-soluble, e.g., sodium, salts), e.g., maleic and citraconic, or the acid anhydrides and acid halides thereof. The acylation is carried out using the acylating agent as solvent, or in the presence of a suitable inert solvent, such as benzene, xylene, dioxane, methylene chloride or the like, particularly when the acylating agent is a solid, and frequently in the presence of a catalyst, such as p-toluenesulfonic acid, or an amine, preferably pyridine. Completion of the reaction can take from a few minutes to 24 hours, depending on the temperature and the solvent employed.

7 If the acylating agent is the free acid, the reaction is preferably carried out in the presence of an esterification catalyst, for example, p-toluenesulfonyl chloride, trifiuoroacetic anhydride, p-toluenesulfonic acid, trifluoroacetic acid, sulfuric acid, and the like.

Thus, for example, 35,165-dihydroxy-1I-lretQ-Sa-prcgn- 17(20)-en-21-oic acid 'y-lactone is reacted with acetic anhydride to obtain 3B-acetoxy-16B-hydroxy-1l-keto 50cpregn-17(20)-en-21-oic acid -lactone.

PREPARATION 1 Methyl 2a-Metl1yL-3-Kez0-1 1fi-Hydroxypregnmfll 7 (20 Diane-21 -Oate To a solution of 8.5 g. (0.025 mole) of Zea-methylllfi-hydroxyprogesterone in 125 ml. of anhydrous tertiary butyl alcohol there is added, With stirring, 13.6 ml. (0.100 mole) of ethyl oxalate and 20 ml. (0.062 mole) of 3.15 normal solution of sodium methoxide in methanol at about 50 C. The mixture is stirred for 20 hours, with the exclusion of moisture, whereupon a solution of 3.06 g. of sodium acetate and 3.53 ml. of glacial acetic acid in 200 ml. of methanol is added thereto.

The thus-obtained solution is cooled to about 5 C. with an ice bath and a solution of 10.8 g. (0.0675 mole) of bromine in 108 ml. of methanol is added during the next half hour. The amount of bromine to be added is determined by the color of the reaction mixture which progressively lightens during the course of the bromine addition until the solution is colorless. When the bromine color appears to persist, no further bromine is added.

To this solution is added 45 ml. (0.142 mole) of a 3.15 Normal methanolic solution of sodium methoxide, followed by stirring for live hours at room temperature, and then 20 ml. of glacial acetic acid and 2.4 g. of zinc dust is added and the mixture is stirred for about 30 minutes. The resulting reaction mixture is poured into about 1500 ml. of water and the precipitate is separated by filtration, washed, and dried to give a product comprising methyl2a methyl-3-keto-1lp-hydroxypregnal,17,(20)- dien-Zl-oate. The pure ester is obtained by dissolving the thus-obtained product in benzene and chromatographing over a column of Florisil (synthetic magnesium silicate), eluting the column with commercial hexanes containing increasing amounts of acetone. The eluted fractions are freed of solvent and those which by papergram and infrared analysis show the desired product, methyl 2a methyl 3 keto 11/3 hydroxypregna 4,17(20)- dien-Zl-oate, are combined and crystallized from, for example, a mixture of ethyl acetate and hexanes.

Similarly, substituting a stoichiometrically equivalent amount of 2a methyl 90c fiuoro 11,8 hydroxyprogesterone, 20c methyl 90 fiuoro 11 ketoprogesterone, and 2a-methyl-4,9(11)-pregnadiene-3,20-dione for 20 methyl 11,3 hydroxyprogesterone in Preparation 1 above is productive of methyl 2oz methyl 3 keto 90c fiuoro its 1ydroxypregna 4,17(20) dien 21 oate, methyl 20c methyl 3,11 diketo 9a fluoropregna 4,

17(20)-dien-21-oate, and methyl 20c methyl 3 ketopregna 4,9(11),17(20) trien-21-oate, respectively.

Similarly, substituting a stoichiometrically equivalent amount of 60a methylprogesterone, 6a methyl 11 B hydroxyprogesterone, 6a methyl 11/3 hydroxy 1,4 pregnadiene 3,20

dione, 6oz methyl 1,4 pregnadiene 3,11,20 trione, 6a methyl 9a fiuoro 1115' hydroxyprogesterone, 6a .ethyl 90c fiuoro 11B hydroxy 1,4 pregnadiene-3,20-dione, 6a methyl 9c; fiuoro 11 ketoprogestcrone,

6a methyl 9o: fiuoro 1,4 pregnadiene 3,11,20

trione,

6m methyl 4,9(11) pregnadiene 3,20 dione and 6e. methyl 1,4,9(11) pregnatriene 3,20 dione for 20: methyl 11B hydroxyprogesterone in Preparation 1 above is productive of methyl 3 keto 6oz methylpregna 4,17(20) dien 21 oate,

methyl 3 keto 6m methyl 11B hydroxypregna 4,

17(20) dien 21 oate,

methyl 3 keto 6a methyl 116 hydroxypregna 1,

4,17(20)-trien-21-oate,

methyl 3,11 diketo 60c methylpregna 1,4,17(20) trien-Z l -oate,

methyl 3 kcto 60 methyl 90a fiuoro 11B hydroxypregna-4,17(20)-dien-21-oate,

methyl 3 keto 6a methyl 90c fiuoro 115 hydroxypregna-1,4,17(20)-dien-2l-oate,

methyl 3,11 diketo 60 methyl 90c fluoropregna 4,

17(20)-dien-21-oate,

methyl 3,11 diketo 60c methyl 9a fluoropregna 1,

4,17(20)-trien-21-oate,

methyl 3 keto 60c methylpregna 4,9(1l),17(20) trien-Zl-oate,

and methyl 3 keto 6m methylpregna 1,4,9(11), 17

(20)-tetraen-21-oate, respectively.

PREPARATION 2 M ethyl 35,1 1 a-DihydroxydwPregn-l 7 20 -En-21 -Oate To a solution of 3.2 g. of 35,1Ia-dihydrQXy-Sa-pregnan-ZO-one in ml. of tertiary butyl alcohol is added at C. with stirring under a nitrogen atmosphere, 5.6 ml. of ethyl oxalate and 4.76 g. of 28.1 percent by Weight sodium methoxide in methanol. The resulting solution is allowed to cool to room temperature and is stirred for 2 hours. Then a solution of 1.44 ml. of acetic acid and 1.66 g. of sodium acetate in m1. of methanol at 10 C. is added over a period of 10 minutes. The resulting solution is cooled to 0 C. and to it is slowly added, over a period of 15 minutes, 3.2 g. of bromine in'48 ml. of cold methanol, followed by 10.7 g. of 28.1 percent by weight sodium methoxide in methanol. After stirring for 1.5 hours While Warming to room temperature, 16 m1. of acetic acid and 3 g. of zinc dust is added and stirring is continued for 30 minutes. After filtering, 50 ml. of water is added to the filtrate and the mixture is concentrated at reduced pressure. The product is extracted with methylene chloride which is then washed with water, aqueous sodium bicarbonate, dried and then chromatographed over Florisil (synthetic magnesium sili cate) and eluted with commercial hexanes containing increasing amounts of acetone. Those eluate fractions shown by infrared and papergram analysis to contain methyl 35,11tt-dihydroxy-5wpregn-17(20)-en 21 oate are combined and recrystallized from for example; a mixture of acetone and hexanes.

Similarly, substituting a stoichiometrically equivalent amount of 3a hydroxy 5e pregnan 20 one,

30.,11,8 dihydroxy 5/3 pregnan 20 one,

30 hydroxy 5B pregnane 11,20 dione, and

3u,11a dihydroxy S B pregnan 20 one for 36,11a-dihydroXy-Sa-pregnan-20-one in Preparation 2 above is productive of methyl 3a hydroxy 5B pregn 17(20) en 21 oate, methyl 3 x,l1B dihydroxy 5B pregn -17(20) en 21 oate, methyl 3oz hydroxy 11 keto 55 pregn 17(20.) en

21-oate, and methyl 301,11 dihydroxy 5B prcgn 17(20) en 21.

oate, respectively.

Similarly, substituting a stoichiometrically equivalent amount of methyl 3fi-hydroxy-16a-methyl-5tx-pregnane- 11,20 -dione for 3fl,110tllllYdI'OXY-SOL-PI'EgHZUI-ZO-OHC in t3; Preparation 2 above is productive of methyl BB-hydroxy- 1 l-keto-l 6a-methyl-5 :x-pregnl 7 (20 -en-2 1 -oate.

PREPARATION 3 Methyl Sp-Hydi'wty-J 6p-Methylpregna-5 (6) ,1 7(20)- Dien-Zl -ate To a stirred solution of 55.8 g. (0.15 mole) of 165- methylpregnenolone acetate in 525 ml. of Warm (60 C.) t-butyl alcohol contained in a nitrogen atmosphere was added 84 ml. (4 equivalents) of ethyl oxalate and 71.4 g. of a 28.1 percent w./w. solution of sodium methoxide in methanol (2.5 equivalents of methoxide). The mixture became cloudy but no precipitation occurred. The temperature was allowed to drop to 2530 C. while stirring for 1 hour. A cold (0 .C.) solution of 21.6 ml. of acetic acid and 24.9 g. of anhydrous sodium acetate in 1050 ml. of methanol was then added and the solution further cooled to 0 C. in a cooling bath. With continued cooling a solution of 72 g. (3 equivalents) of bromine in 720 ml. of cold methanol was added over a period of 15 minutes. The solution was then treated rapidly with 190.5 g. of a 28.1 percent w./w. solution of sodium methoxide in methanol (6.6 equivalents of methoxide). The color became orange-red soon fading to amber. The cooling bath was removed, and the solution stirred for 2 hours, 150 ml. of acetic acid and 60 g. of zinc dust were then added and the mixture was stirred for 30 minutes. The mixture was then filtered. The filtrate was evaporated to a thick paste which was partitioned between methylene chloride and water. The organic phase was dried and evaporated to a syrup which was taken up in benzene and chromatographed on 1 kg. of Florisil. The column was eluted with one 1800-1111. portion of benzene, four 1800- ml. portions of 2 percent acetone in commercial hexanes, fifteen l800-ml. portions of 3 percent acetone in commercial hexanes and 1300 ml. of acetone. Fractions 1-20 upon evaporation gave partly crystalline material and were combined to yield 40.98 g. of a product comprising methyl 3 B hydroxy-16fi-methylpregna-5 (6) ,17 (20) -dien- 21-oate. A portion was rechromatographed on Florisil and the combined product fractions crystallized from dilute methanol to give a product melting at 8391 C. Repeated recrystallization from methanol yielded methyl 3 fi-hydroxy 16/3 methylpregna-S (6) ,17(20)-dien-21- oate having a melting point of 151153 C.,

[ab-30 (CHCl A313 226m =11,100)

and the following analysis:

Analysis.Calcd. for C H O C, 77.05; H, 9.56. Found: C, 76.67; H, 9.62.

Similarly, substituting a stoichiometrically equivalent amount of 6 methyl 3p acetoxy-5-pregnen-20-one for 16Bmethylpregnenolone acetate in Preparation 3 above is productive of methyl 3fl-hydroxy-6-methylpregna-5(6), l7(20)-dien-2l-oate.

PREPARATION 4 Methyl 3-Ket0-1JB-Hydroxy-l6tt-Methylpregna- 4,17(20)-Dien-21-Oate (A) A mixture of 1.0 g. of methyl 3,11-dlketQ-'16OC- methylpregna-4,17(20)-dien-2l-oate, mg. of paratoluenesulfonic acid, 5 ml. of ethylene glycol and 100 ml. of benzene is heated under reflux for 5 hrs. with vigorous stirring. The water formed is removed by codistillation' 5 ml. of 0.1 N sodium hydroxide and 0.5 g. of sodium borohydride is added and stirring is continued for about an additional 24 hours. The solvent is removed by distillation at reduced pressure and the residue is triturated with water and then recrystallized from, for example, a mixture of acetone and water to give the 3-ethylene ketal of methyl 3-keto-11fi-hydroxy 16a methylpregna 4,17 (20)-dien-21-oate.

(C) To a solution of 1.0 g. of the 3-ethylene ketal of methyl 3 keto-l lfl-hydroxy-16et-methylpregna-4,17(20)- dien-21-oate in ml. of acetone is added sutficient 6 N hydrochloric acid to give an acidic test with pH test paper. The mixture is heated under reflux for about 30 minutes, the solvent removed by distillation under reduced pressure, and the residue extracted with methylene chloride. The methylene chloride solution is washed with water, dried, and chromatographed over Florisil (synthetic magnesium silicate). The column is eluted with portions of commercial hexanes containing increasing amounts of acetone. Those eluate fractions containing methyl 3- keto-l lfl-hydroxy 160a methylpregna 4,17 (20) dien- 2l-oate as shown by infrared and paper chromatography analysis are combined and crystallized, for example, from ethyl acetate, to obtain the pure compound.

Substituting a stoichiometrically equivalent amount of iethyl 36 hydroxy-l1-keto-5ot-pregn-17(20)-en-21-oate for the B-ethylene ketal of methyl 3,1l-diket0-16a-methylpregna-4,17(20)-dien-21-oate in Part B of Preparation 4 above is productive of methyl 3 ,8,1lfi-dihydroxy-5ot-pregnl7(20)-en-2l-oate.

Similarly, substituting as stoichiometrically equivalent amount of methyl 36-hydroxy-l l-lreto 16 methyl-5ozpregn-17(20)-en-2l-oate for the S-ethylene ketal of methyl 3,11-dil-:eto-16a-methylpregna-4,17(20)-dien-21-oate in Part B of Preparation 4 above is productive of methyl 3 5,1 lfi-dihydroxy-16-methyl-5ot-pregn-17(20)-en-2l-oate.

PREPARATION 5 Methyl 3-Keto-9a-Fluoro-11fi-Hydroxypregna-1,4,17(20)- Trien-21-Oate steep liquor (60 percent solids) and tap water is adjusted to a pH of 4.9. This medium is sterilized for 45 minutes at 15 pounds per square inch pressure and inoculated with a one to two day growth of Septomyxa afiim's A.T.C.C. 6737. The Erlenmeyer flasks are shaken at room temperature at about 24 C. for a period of 3 days. At the end of this period, this 600-ml. volume is used as an inoculum for 10 liters of the same glucose-corn steep liquor medium which in addition contained 10 ml. of an antifoam (a mixture of lard oil and octadecanol). The fermentor is placed into the water bath, adjusted to 28 C., and the contents stirred (300 rpm.) and aerated (0.5 liter air/ 10 liters beer). After 17 hours of incubation, when a good growth developed and the acidity rose to pH 6.7, 2 g. of methyl 3-keto-9ot-fluoro-llflhydroxy-aregnaA,17(20)-dien-2l-oate plus 1 g. of 3- l etobisnor-4-cholen-22-al, dissolved in ml. of dimethylformamide, is added and the incubation (conversion) carried out at the same temperature and aeration for 24 hrs. (final pH 7.9). The myceluim is filtered off and the steroidal material is extracted with methylene chloride, the extracts evaporated to dryness, and the resulting residue chromatographed over a Florisil (syn thetic magnesium silicate) column, and eluted with com mercial hexanes containing increasing amounts of acetone. The eluate fractions are evaporated and the residues containing methyl 3-lreto-9ct-fluoro-l lfi-hydroxypregna-1,4,17(20)-trien-'2l-oate as shown by paper chromatography and infrared absorption are combined and recrystallized, for example, from ethyl acetate-hexane mixture.

Similarly, substituting Methyl 3 -leto-l 1 B-hydroxy- 1 6oc-methylpregna-4, 1 7 (20 dien-21-oate,

Methyl 3, l l-diketo-16ct-methylpregna-4, 17 (20) -dien-21- oate,

Methyl 3-keto-l6ot-methylpregna-4,9 l l ,l7(20)-trien- 21 oate; and methyl 3-keto-9a-fiuoro-1 1 p-hydroxyl6a-methylpregna-4,l7(20)-dien-2l-oate for Methyl 3-keto-9 ot-iluoro- 1 l {3-hydroxypregna-4, l 7 (20) dien-2 l-oate in Preparation above is productive of Methyl 3-keto-l lfi-iydroxy-16ot-methylpregna-l ,4,

17 (20) -trien-21-oate,

Methyl 3 ,1 l-diketo-16ot-methylpregna-L4, 17 (20 -trien- 2 l-oate,

Methyl 3-keto-l6ot-methylpregna-1,4,9(l1),l7(20)- tetraen-Z l-oate, and methyl 3-keto-9a-fiuoro-l1 8- hydroxy-lfitx-methylpregna-lA, 17 (20) -trien-2 l-oate, respectively.

PREPARATION 6 A mixture of l g. of methyl 3-keto-1lfl-hydroxydmtmethylpregna-4,l7(20)-dien-2l-oate, 650 mg. of N-bromoacetamide and 6 ml. of pyridine is stirred in the dark for a period of 30 minutes. The mixture is cooled in an ice water bath and a stream of sulfur dioxide is directed onto the surface of the stirred mixture until a negative potassium iodide-starch test is obtained. Fifty ml. of water is then added to the mixture and the mixture is maintained at about 05 C. for about 30 minutes'. The precipitated solid is separated by filtration and crystallized from, for example, acetone-water to obtain methyl 3-keto-l6e-methylpregna-4,9(ll),l7(20)- trien-iZl-oate.

PREPARATION 7 One half gram of methyl 3-keto-lGtx-methylpregna- 4,9(11),17(20)-trien-2l-oate is dissolved in 20 ml. of methylene chloride and thereto is added a solution of 1 ml. or" 71 percent perchloric acid in ml. of water and 200 mg. of N-bromoacetamide in 50 ml. of tertiary butyl alcohol. The solution is maintained at room temperature for minutes and then mixed with a solution of 0.3 g. of sodium sulfite in 12 ml. of water. The mixture is distilled at reduced pressure until the residual solution becomes cloudy. The product is then precipitated by the addition of 100 ml. of a mixture of icewater. The crystalline precipitate is filtered, washed with water and then dried and recrystallized from a mixture is distailled at reduced pressure until the residual methyl 3k6l0-90t-bl'OlTlO-1 lfi-hydroxy-16a-methylpregna- 4,l7(20)-dien-2l-oate.

A mixture of 0.45 g. of methyl 3-kcto-9a-bromo-ll5- hydroxy-l6a-pregna-4,l7(20)-dien-2l-oate, 0.45 g. of anhydrous potassium acetate and ml. of acetone is heated at its refluxing temperature for a period of 5 hrs. The mixture is then cooled and poured into water and extracted with methylene chloride. The methylene chloride extract is dried and poured over a column of g. of Florisil (synthetic magnesium silicate). The column is developed with commercial hexanes containing, increasing portions of acetone. The eluates are evaporated to dryness and those fractions shown by infrared and papergram analysis to contain methyl 3-l eto-9(ll) oxido-l6a-methylpregna-4,l7(20)-dien-2l-oate are combined and crystallized, for example, from acetone-hexanes mixture.

One gram of methyl 3-keto-9(11)-oxido-16a-methylpregna-4,17(20)-dien-21-oate is dissolved in ml. of methylene chloride and thereto is added 5 ml. of 48 percent hy rofiuoric acid. The mixture is stirred vigorously for 6 hrs. and then poured into an excess of cold aqueous 5 percent sodium bicarbonate solution. The methy lene chloride layer is separated, dried over anhydrous sodium sulfate and then poured onto a column of g. of Florisil (syntheic magnesium silicate). The column is developed with commercial hexanes containing increasing portions of acetone. The eluates are evaporated to dryness and those fractions shown by infrared and papergram analysis to contain methyl 3-keto- 9c: fiuoro 11p hydroxy 16a methylpregna 4, l7(20)-dien-2l-oate are combined and recrystallized, for example, from acetone-hexanes mixture.

PREPARATION 8 Methyl 3,11-Diketo-9a-Flu0r0pregna 4,17(20)- Dian-21 -Oate A solution of 2 g. of methyl 3-keto-9ot-fluoro-llfihydroxypregna-4,l7(20)-dien-2l-oate in ml. of acetic acid at 20 is prepared. To this solution is added dropwise 0.41 g. of chromium trioxide in 41 ml. of acetic acid and 0.4 ml. of water. The temperature is maintained at 19 to 23 C. during the addition and for one and onehalf hours thereafter. The reaction mixture is diluted with 600 ml. of water and extracted with six 100-m1. portions of methylene chloride which are combined. The combined extracts are washed with dilute sodium bicarbonate solution. and water, dried and evaporated to dryness under reduced pressure. Recrystallization of the solid residue from methanol gives methyl 3,11-diketQ-90t' fiuoropregna-4,l7(20)-dien-2l-oate.

Similarly, substituting a stoichiometrically equivalent amount of methyl 3-keto-9a-fiuoro-1lfi-hydroxypregnal,4,-l7(20) trien 2l-oate for methyl 3-keto-9a-fiuorollfi-hydroxypregnat,l7(2O)-dien-21-oate in Preparation 8 above is productive of methyl 3,1l-diketo-9a-fluor0- pregna-l,4,l7(20)-trien-2l-oate.

Similarly, substituting a stoichiometrically equivalent amount of methyl 3-kcto-9a fiuoro llfl hydroxy-l6amethylprcgna-4,l7(20)-dien-2l-Oate and methyl 3-keto- 9a-tluoro-l1fi-hydroxy a methylpregna l,4,l7(20)- trien-2l-oate for methyl 3-keto-9a-fiuoro llfl hydroxypregna-4,1'7(20)-dien-21-oate in Preparation 8 above is productive of methyl 3,11 diketo 16a methylpregna- 4,l7(20)-dien-2l-oate and methyl 3,1l-diketo-16a-methylpregnal ,4, 17 (2O) -trien-2 l-oate, respectively.

EXAMPLE 1 SBJQB'Dz'hydFOxy-I1-Ket0-5a-Prcgn-17(20 -En-21-Oic Acid 'y-Lactonc and the 3fl-Acet0xy Derivative Thereof 1A. 3/3-HYDROXY-1l-KETO-5a-PREGN-l6(17)-EN- 21-OIC ACID To a solution of 29.1 g. of methyl 3/3-hydroxy-l1-keto- 5tx-pregn-17(20)-en-2l-oate in 350 ml. of methanol there was added a solution of 29.1 g. of potassium hydroxide in 100 ml. of water. The reaction mixture was then heated under reflux for about 3 hours, cooled, poured into water, and extracted with methylene chloride. The alkaline aqueous solution, comprising 3 B-hydroxy-l l-keto- 5tx-pregn-16( l7)-en-2l-oic acid, obtained from the extraction was acidified with dilute hydrochloric acid and extracted with several portions of ethyl acetate. The ethyl acetate extracts were combined, Washed with water until neutral, dried over sodium sulfate, followed by removal of the solvent in vacuo to give a residue. The residue was then fractionally crystallized from acetone and yielded a first crop of crystalline material. The mother liquor remaining was taken to dryness leaving a residue which was crystallized from ether to give a second crop of crystalline material. The crystalline material obtained from the acetone crystallization (first crop) and from the other crystallization (second crop) were combined to give 6.95 g. of 3fi-hydr0xy-ll-keto-5a-pregn-l7(20)-en- 2loic acid having a melting point of 270-276 C., which upon recrystallization from methanol had a melting point of 273-276 C.

3,8-hydroxy-ll-keto-Su-pregn l7(20)-en-21-oic acid is reesterified, according to procedures known in the art for the esterification of steroid free acids, such as those dis- 13 closed by Reindel and Niederlander, Ber. 6813, 1969-73 (1935) to give the corresponding 21-methyl ester, which is then recycled as the starting material in the abovedescribed reaction.

The mother liquors from the ether crystallization yielded a third crop (8.16 g., melting point 176-l84 C.) of crystals comprising 3,8-hydroxy-11-keto-5u-pregn-16( 17 en-21-oic acid. Two recrystallizations of the third crop from acetone-commercial hexanes gave an analytical sample of 3,8-hydroXy-1l-keto-5a-pregn-16(17)-en-21-oic acid having a melting point of 188l90 C., infrared absorption bands (Nujol) a t 3450, 3370, 2720, 2600, 1725, 1700, 1210, 1170 and 1030 cm. and the following analysis:

Analysis.-Calcd. for c u o c, 72.80; H, 8.73. Found: C, 72.64; H, 8.87.

Similarly, substituting a stoichiometric equivalent amount of the starting materials used for the preparation of the compounds of Formula 1, namely,

Methyl 3-ketopregna-4, 17 (20) -dien-21-oate,

Methyl 3-ketopregna-1,4,17(20) -trien-21-oate,

Methyl 3-keto-l 1,8-hydroxypregna-4, 17 (20 -dien-21-oate,

Methyl S-keto-l 1B-hydroxypregna-1,4,l7 (20) -trien-21- oate,

Methyl 3 ,1 l-diketopregnal, 1 7 (20) -dien-2 l-oate,

Methyl 3,11-diketopregna-1,4,17(20)trien-21-oate,

Methyl 3-keto-9a-fluoro-l l fi-hydroxypregna- 1 ,4, 17 (20 trien-Zl-oate,

Methyl 3,1 1-diketo-9a-fiuoropregnai,17(20) -dien-21- oate,

Methyl 3,1 1-diketo-9a-fluoropregna-1,4,17(20) -trien-21- oate,

Methyl 3-ketopregna-4,9(l1),17(20)-trien-21-oate, and

Methyl 3-ketopregna-1,4,9(11),l7(20)-tetraen-21-oate for methyl 3 8-hydroxy 11 keto 5ocpregn-17(20') -en-21- oate in Example 1A above is productive of the A compounds useful as intermediates in the production of the compounds of Formula 1 and the 2l-free acids otherwise corresponding to the 21-methyl ester starting material used for the preparation of the compounds of Formula 1 namely,

3-ketopregna-4,l6 17)-die11-21-oic acid and 3-ketopregna-4,17(20)-dien21-oic acid,

3-ketopregna-l,4,16(17)-trien-21-oic acid and 3-keto-pregna- 1 ,4, 17 20) -trien-2 1-oic acid 3-keto-1 lfi-hydroXypregna-4,16(17)-dien-21-oic acid and 3-keto-1 1fi-hydroxypregna-4, 17( 20) -dien-21-oic acid,

3-keto-1lfl-hydroxypregna-1,4,16(17)-trien-21-oic acid and 3-keto-1l{3-hydroxypregna-L4,17(20)-trien-21-oic acid,

3,1 l-diketopregna-4,l6 17 -dien-21-oic acid and 3 ,1l-diketopregna-4,17(20)-dien-21-oic acid,

3,1 1-diketopregna-l,4,16(17)-trien-2l-oic acid and 3,1l-diketopregna-1,4,17(20)-trien-21-oic acid,

3-keto-9a-tluoro-l lfi-hydroxypregnar, 16 17 -dien-2 l-oic acid and 3 -keto-9 a-fluoro-l -hydroXypregna-4,17(20) -dien-21-oic acid,

3-keto-9 oc-flUOIO-l l fl-hydroxypregna- 1 ,4, 17 (20 -trien- 21-oic acid,

3,1 l-dil eto-9a-fiuoropregnal,16(17)-dien-2l-oic acid and 3,11-diketo-9a-fiuoropregnal,17(20)-dien-2l-oic acid,

3,1 l-diketo-9a-fluoropregna-1,4,16( 17 -trien-2l-oic acid and 3,1 l-dilreto-9a-fluoropregna-1,4,17 (20)-trien-21-oic acid,

3-ketopregna-4,9 1 1 ,16 17 -trien-21-oic acid and 3-ketopregna-4,9(l1),17(20)-trien-21-oic acid, and

3-ketopregna-l,4,9(11),16(17)-tetraen-21-oic acid and 3-l etopregna-l,4,9 1 l ,17(20) -tetraen-21-oic acid,

respectively. Similarly, substituting a stoichiometric equivalent amount of the starting materials used for the preparation of the compounds of Formula 2a, namely,

Methyl Zea-methyl 3 keto-l1{3-hydroxypregna-4,l7(20)- dien-2l-oate,

Methyl 20c methyl-3-1l-diketopregna 4,17 (20) -dien-21- oate,

Methyl Zea-methyl 3 keto-9a-fluoro-llfi-hydroxypregna- 4,17(20)-dien-21-oate,

Methyl 20c methyl-3,11-diketo-9a-fiuoropregna-4,17(20)- dien-21-oate, and

Methyl 2a-methyl-3-ketopregna-4,9 1 l ,17 (20) -trien-21- oate for Methyl 3 B hydroxy-l1-keto-5a-pregn-17(20)-en-21-oate in Example 1A above is productive of the A compounds useful as intermediates in the production of the compounds of Formula 2a and the 21-free acids otherwise corresponding to the 2l-methyl ester starting material used for the preparation of the compounds of Formula 2a, namely,

Zea-methyl 3 keto-l113-hydroxypregna-4,16(17)-dien-21- oic acid and 20a methyl-3-keto-1lfl-hydroxypregna 4,17(20)-dien-21- oic acid,

20: methyl-3,11-diketopregna 4,16(17)-dien-21-oic acid and 2a-methyl-3,1 l-diketopregna-4,l7(20) -dien-21-oic acid,

204 methyl 3 keto c fluoro 11,8 hydroxypregna- 4,16(17)-dien-21-oic acid and 20a methyl 3 keto 90: fluoro 11B hydroxypregna- 4,17(20)-diene-21-oic acid,

2a methyl-3,1l-diketo-9a-flu-oropregnal,16(17)-dien-2loic acid and 20a methyl-3,1l-diketo-9a-fluoropregna-4,17(20)-dien-2l oic acid, and

2a methyl-3-ketopregna-4,9 1 1 ,16 17) -trien-21-oic acid and 2m-methyl-3-ketopregna-4,9 11),17(20)-trien-21-oic acid,

respectively.

Similarly, substituting a stoichiometric equivalent amount of the starting materials used for the preparation of the compounds of Formula 2b, namely,

Methyl 3-keto-6ot-methylpregna-4,17 (20) -dien-2l-oate,

Methyl 3-keto 6a methyl-1lfl-hydroxypregna-4,17(20)- dien-21-oate,

Methyl 3 keto-6a-methyl-11fl-hydroXypregna-1,4,17(20)- trien-21-oate,

Methyl 3,11-diketo 60c methylpregna-4,17(20)-dien-21- oate,

Methyl 3,11 diketo-6amethylpregna-1,4,17 (20)-trien-21- oate,

Methyl 3-keto-6u-methyl 9a fiuoro-l lfl-hydroxypregna- 4,17(20)-dien-2l-oate,

Methyl 3-keto-6a-methyl 90c fluoro-l lfl-hydroxypregna- 1,4,17(20) -trien-21-oate,

Methyl 3,11 diketo-6a-methyl-Qu-fiuoropregnal,17(20) dien-21-oate,

Methyl 3 ,11-diketo-6a-methyl-9a-fluoropregna-1,4,17(20)- trien-Zl-oate,

Methyl 3-keto-6ot-methylpregna-4,9(l1),17(20)-trien-21- oate, and

Methyl 3-keto-6ot-methylpregna-1,4,9(11),17 (20 -tetraen- 21-oate for methyl 3fi-hydroXy-11-keto-5a-pregn-1(20)- en-21-oate in Example 1A above is productive of the A compounds useful as intermediates in the production of the compounds of Formula 2b and the 21-free acids otherwise corresponding to the 21-methyl ester starting material used for the preparation of the compounds of Formula 2b, namely, 3-keto-6ot-methylpregna-4,16(l7)dien-21-oic acid and 3-keto-6a-methylpregna-4,17(20)-dien-21-oic acid, 3 keto-6u-methyl-l lfi-hydroxypregna 4,16( 17) -dien-2loic acid and 3 keto-6a-methyl-11,6-hydroxypregna 4,17(20)-dien-21- oic acid,

3-keto-6u-methyl-1 l B-hydroxypregna-1,4,17 -trien-2 1- oic acid and 3 -keto-6u-methyl-1 1fl-hydr0xypregna-1,4,l6( 17) -trien-21- oic acid,

3,11-diketo 6a methylpregna-4,16(17)-dien-21-oic acid and 3,11-diketo-6a-methylpregna-4,17(20)-dien-21-oic acid,

3,11-diketo-6a-methylpregna-1,4,16(17)-trien-21-oic acid and 3,11-diketo-6a-methylpregna-1,4,17(20)-trien-2l-oic acid,

3 keto 60c methyl 9a fiuoro 11p hydroxypregna- 4,l6(17)-dien-2l-oic acid and 3 keto 6a methyl 9a fluoro 11d hydroxypregna- 4,l7(20)-dien-2l-oic acid,

3 keto 6o: methyl 90c fluoro 115 hydroxypregna- 1,4,16(17)-trien-21-oic acid and 3 keto 6oz methyl 90c fiuoro 115 hydroxypregna- 1,4,17(20)-trien-2l-oic acid,

3 l1 diketo-6ot-methyl-9oz-fiuoropregna-4,l6 17)-dien-21- oic acid and 3 ,11 diketo-6ot-methyl-9a-fluoropregna-4,17(20)-dieu-2loic acid,

3,11 diketo-6a-methyl-9a-fiuoropregna-1,4,16(17)-trien- 21-oic acid and 3,11 diketo-6a-methyl9a-fluoropregna-1,4,17(20)-trien- 21-oic acid,

3-keto-6oc-methylpregna-4,9( 11),16(17)-trien'-2l-oic acid and 3 keto-6oc-methylpregna-4,9(11),17(20)-trien-21-oic acid,

and

3 keto-a-methylpregna-1,4,9(11),16(17)-tetraen-21-oic acid and v 3 keto-6u-metl1ylpregna-l,4,9(11),17(20)-tetraen-21-oic acid, respectively. Similarly, substituting a stoichiometric equivalent amount of the starting materials used for the preparation of the compounds of'Formula 2c, namely,

Methyl 3-keto-llp-hydroxy-l6fl-methyland methyl 3- -keto-1 1,6-hydroxy-16ot-methylpregna-4, 17 (20) -dien-21- oate,

Methyl 3-keto-1lfi-hydroxy-lfi S-methyland methyl 3- keto 1lfl-hydroxy-lGu-methylpregua-IA,17(20)-trien- 21-oate,

Methyl 3,11-diketo-16B-methyland methyl 3,11-diketo 16u-methylpregna-4,17 (20)-dien-21-oate,

Methyl 3,11-diketo-l6fl-methyland methyl 3,11-diketo- 16a-methylpregna-1,4,17(20)-trien-21-oate,

Methyl 3 keto-9a-fluoro-1lB-hydroxy-16fi-methyland methyl 3 -lteto-9 tZ-fiUOI'O-l lB-hydroxy- 1 Ga-methylpregna-4,17(20)-dien-21-oate,

Methyl 3,11-diketo-9u-fluoro-165-methyland methyl 3,11 diketo 90c fluoro-16a-methylpregna-4,17(20)- dien-Zl-oate,

Methyl 3,11-diketo-9a-fiuoro-16fi-methy1- and methyl 3,11 diketo 9a fluoro-l6a-'nethy1pregna-1,4,17(20)- trien-Zl-oate,

Methyl 3-keto-16/3-metl1yland methyl 3-keto-16ot-methylpregna-4,9(11),17(20)-trien-21-oate, and

Methyl 3-keto-16l3-methyland methyl 3-keto-16oc methylpregna-1,4,9(11),17(20)-tetraen-21-oate for methyl 3fi-hy-droxy-11-keto-5a-pregn-17(20)-en-21-oate in Example lA above is productive of the A compounds useful as intermediates in the production of the compounds of Formula 2c and the 21-free acids otherwise corresponding to the 2l-rnethyl ester starting material used for the preparation of the compounds of Formula 2c, namely, 3-keto-1lfl-hydroxy-l6-methylprenga-4,16 (17)-dien-21-oic acid and 3-keto-11fl-hydroXy-16B- methyland 3-keto-1lfi-hydroxy-6a-methylpregna-4,17 (20)-dicn-2l-oic acid.

3 keto 11 5 hydroxy-l6-methylpregna-1,4,l6(17)-trien- 21-oic acid and 3-keto-1 lfi-hydroxy-16fl-methyland 3 keto 11 9 hydroxy-16a-methylpregna-1,4,l7(20)- trien-21-oic acid,

3,11 diketo 16-methylpregna-4,l6(17)-dien-2l-oic acid and 3,1l-diketo-16fi-methyl and 3,11-diketo-l6a-methylpregna-4,17(20)-dien-21-oic acid,

3,11 diketo-16-rnethylpregna-1,4,16(17-trien-2l-oic acid and 3,11-diketo-16fi-methyl and 3,1l-diketo-16a-methylpregna-1,4,17(20)-trien-21-oic acid,

3,11 diketo 9a fiuoro-16-methylpregna-4,l6(17)-dien- 2l-oic acid and 3,1l-diketo-9a-fluoro-16fi-methyland 3,11 diketo-9a-fiuoro-16e-methylpregna-4,17(20)-dien- 21-oic acid,

3,11 diketo9a-fluoro-16-methylpregna-1,4,16(17)-trien- 21-oic acid and 3,11-diketo-9a-fluoro-16B-methyland 3,11 diketo c fluoro-16a-mcthylpregna-l,4,17(20)- trien-Zl-oic acid,

3-keto- 1 6-methylpregna-4,9 (1 1)-,16(17)-trien-21-oic acid and 3-keto-l6/3-methyland 3-keto-16m-methylpregna-4,9(11),

17(20)-trien2l-oic acid, and

3 keto-16-methylpregna-1,4,9(11),16(17)-tetraen-2l-oic acid and 3-keto-l6fl-methyland 3-keto-l6a-methylpregna-l,4,9

(l1),17(20)-tetraen-21-oic acid, respectively.

Similarly, substituting a stoichiometric equivalent amount of the starting materials used for the preparation of the compounds of Formula 3, namely,

Methyl 3-keto-l1a-hydroxypregna-4,17(20)-dien-2l-oate and methyl 3-keto-1lu-hydroxypregna-lA,17(20)-trien- 2l-oate for methyl 3/3-l1ydroxy-l1-keto-5ot-pregn-17 (20)-en-21-oate in Example 1A above is productive of the A compounds useful as intermediates in the production of the compounds of Formula 3 and the ZI-free acids otherwise corresponding to the Ill-methyl ester starting material used for the preparation of the compounds of Formula 3, namely,

3-keto-11a-hydroxypregna-4,16(17)-dien-21-oic acid and 3-keto-l1u-hydroxypregna-4,17(20)-dien-21-oic acid, and

3 keto l1whydroxypregna-1,4,l6(17)-trien-21-oic acid and 3 keto 1loc-hydroxypregna-lA,l7(20)-trien-2l-oic acid,

respectively.

Similarly, substituting a stoichiometric equivalent amount of the starting materials used for the preparation of the compounds of Formula 4a namely,

Methyl 3 B-hyclroxy-S u-pregn- 1 7 20 -en-2 l-oate,

Methyl 35,115 dihydroxy 4 5a-pregn-17(20) -en-21-oate,

and

Methyl 35,11u-dihydroxy-5ot-pregn-17(20)-en-21-oate for methyl 3,8 hydroxy 11 keto-5a-pregn-17(20)-en-2loate in Example 1A above is productive of the A compounds useful as intermediates in the production of the compounds of Formula 4a and the 21-free acids otherwise corresponding to the ZI-methyl ester starting material used for the preparation of the compounds of Formula 4a, namely,

3B-hydroxy-5a-pregn-16(17)-en-21-oic acid and 3B-hydroxy-5a-pregn-17(20)-en-21-oic acid,

3B,11,8-dihydroxy-5ot-pregn-16(17)-en-21-oic acid and 3,8,11fl-dihydroxy-5ot-pregn17(20)-en-21-oic-acid, and

313,11ot-dihydroxy-5a-pregn-16(17)-en-21-oic acid and 36,1la-dihydmxy-Sa-pregn-l7(20)-en-21-oic acid, respec-.

tively.

Similarly, substituting a stoichiometric equivalent 1 7 amount of the starting materials used for the preparation of the compounds of Formula 411, namely, Methyl 3u-hydroxy-55-pregn-17(20)-en-21-oate, Methyl 3a,115-dihydroxy-55-pregn-17 (20)-en21-oate, Methyl 30c hydroxy-l1-keto-55-pregn-l7(20)-en2l-oate and Methyl 3 a, 1 1a-dihydroxy-55-pregn- 17 (20) -en-2l-oate for methyl 3 5-hydroxy-1 l-keto-S a-pregn-l 7 -en-21-oate in Example 1A above is productive of the A compounds useful as intermediates in the production of the compounds of Formula 4b and the 21-free acids otherwise corresponding to the ZI-methyl ester starting material used for the preparation of the compounds of Formula 4b, namely, 3a-hydroxy-55-pregn-16t17)-en-21-oie acid and 3u-hydroxy-55-pregn-17 (20) -en-21-oic acid, 304,115-dihydroxy-55-pregn-16(17)-en-21-oic acid and 3 OL,1 l5-dihydroxy-55-pregn-17 (2G) -en-21-oic acid, 3u-hydroxy-l-l-keto-55-pregn-l6(17)-en-2l-oic acid and 3a-hydroxy-l 1-keto-55'pregn-17 (20)-en-21-oic acid, and 3a,11m-dihydroxy-55-pregn-16(17)-en-21-oic acid and 3a,1'1a-dihydroxy-55-pregn-17(20)-en-21-oic acid, respectively.

Similarly, substituting a stoichiometric equivalent amount of the starting materials used for the preparation of the compounds of Formula 5a, namely,

Methyl 35,115-dihydroXy-l65-methyland methyl 35,115-

dihydroxy-l6a-methyl-5a-pregn-17(20)-en-21-oate and Methyl 35-hydroxy-11-keto-l65-methyland methyl 35- hydroxy 11 keto-l 6a-methyl-5a-pregn-17(20)-en-21- oate for Methyl 35-hydroxy-1 1-keto-5oc-pregn-l7 (20) -en-2 l -oate in Example 1A above is productive of the A compounds useful as intermediates in the production of the compounds of Formula 5a and the 2l-free acids otherwise corresponding to the ZI-methyl ester starting material used for the preparation of the compounds of Formula 5a, namely,

35,115 dihydroxy 16-methyl-5a-pregn-16(17)-en-21-oic acid and 35,1l5-dihydroxy-l65-methyland 35,115-dihydroxy-16ocmethyl-Sa-pregn-U'QO)-en-21-oic acid, and

35 hydroxy 1l-lieto-16-methyl-5 ot-pregn-l 6(17)-en-21- oic acid and 35-hydroxy-l'l-keto-l65-methyland 35- acid, respectively.

Similarly, substituting a stoichiometric equivalent amount of the starting materials used for the preparation of the compounds of Formula 5 b, namely,

Methyl 3a,1l5-dihydroxy-165-methyland methyl 305,115-

dihydroxy-l 6a-methyl-55-pregn-17 (20 -en2-1-oate and Methyl 3a-hydroxyl1-keto-165-methyland methyl chydroxy ll keto-l6a-methyl-S5-pregn-17(20)-en-21- oate for Methyl hydroxy-1l-keto-5a-pregn-17(20)-en-21-oate in Example 1A above is productive of the A compounds useful as intermediates in the production of the compounds of Formula 5 b and the ZI-free acids otherwise corresponding to the 21-methyl ester starting material used for the preparation of the compounds of Formula 5b, namely,

30,l 15 dihydroxy 16-methy1-55-pregn-l6(17)-en-21-oic acid and 3a,l15-dihydroxy-165-methyland 304,1 l5-dihydroxy-16amethyl-55-pregn-l7t20)-en-2 l-oic acid, and

3 oc-hYdIOXY-l 1-keto-16-methyl-55-pregn-16 17 -en-2l-oic acid and 3a-hydroxyll-keto-165-methyland Bot-hydroxy 11 keto-l6a-methyl-55-pregn-l7(20)-en-2'1-oic acid, respectively.

Similarly, substituting a stoichiometric equivalent amount of the starting materials used for the preparation of the compounds of Formula 6, namely,

Methyl 3 5-hydroxypregna-5 6 17 (20) -dien-Z1-oate, Methyl 35,115 dihydroxypregna '5(6),l7(20)-dien-21- oate,

Methyl 35 hydroxy-1 l-ketopregna-S (6),17 20) -dien-2loate and Methyl 35,11a-dihydroxypregna-5 (6) ,17 (20) -dien-2l-oate for methyl 35-hydroxy-l'1-keto-5a-pregn-17(20)-en-21- oate in Example 1A above is productive of the A compounds useful as intermediates in the production of the compounds of Formula 6 and the Zl-free acids otherwise corresponding to the ZI-methyl ester starting mate rial used for the preparation of the compounds of Formula 6, namely,

35-hydroxypregna-5 (6 ,1 6 l 7)-clien-2 l-oic acid and 3 5-hydroxypregna-5 6 1 7 20) -dien-21-oic acid,

35,115-dihydroxypregna-5(6),16(17)-dien-2l-oic acid and 3 5-1 l5-dihydroxypregna-5 6) 17 (20) -dien-2l-oic acid,

35 hydroxy-l l-ketopregna-S (6),16 (17)-dien-2l-oic acid and 1 35 hydroxy-l l-ketopregna-S {6),17 (20)-dien-2l-oic acid,

and

3fi,110t dihydroxypregna-S (6),16(17) dien Zl-oic acid and 35,11a-dihydrQXypregna-S(6),17(20)-dien*21-oic acid, re-

spectively.

Similarly, substituting a stoichiometric equivalent amount of the starting materials used for the preparation of the compounds of Formula 7a., namely,

Methyl 35-hydroxy-6-methylpregna-5 (6),l7(20)-dien-21- oate,

Methyl 35,115 dihydroxy-6-methylpregna-5 (6),17(20)- dien-Zl-oate and Methyl 3 5-hydroxy-6-methylll -ketopregna-5 (6) 17 (20) dien-Zl-oate for Methyl =3 5-hydroxy- 1 l-keto-5a-pregn-1 7 (20 -en-2 l-oate in Example 1A above is productive of the A compounds useful as intermediates in the production of the compounds of Formula 7a and the Zl-free acids otherwise corresponding to the 2l-methyl ester starting material used for the preparation of the compounds of Formula 7a, namely,

3 5-hydroxy-6-methylpregna-S 6) ,16( 17) -dien-21-oic acid and 3 5-hydroxy-6-methylpregna-5 (6 ,17 (20) -dien-21-oic acid,

35,115 dihydroxy-6-methylpregna-5(6),l6(17)-dien-21- oic acid and 35,115 dihydroxy-6-methylpregna-5:(6) ,17 (20)-dien-2loic acid, and

3 5-hydroxy-6-methyl-1 1-ketopregna-5-(6) ,16( 17)-dien-2loic acid and 35 hydroxy 6-methyl-l1-ketopregna-5(6),l7(20)-dien- 21-oic acid, respectively.

Similarly, substituting a stoichiometric equivalent amount of the starting materials used for the preparation of the compounds of Formula 7b, namely,

Methyl 35-hydroxy-l65-methyland methyl 35-hydroxy- 16a-methylpregna-5 6) 17 (2t) -dien-21-oate,

Methyl 35,115-dihydroxy-165-m-ethyland methyl 35,115-

dihydroxy 16cc methylpregna 5(6),17,(20) dien- 21-oate, and

Methyl 3 5-hydroxy-11-keto-l65-methyland methyl 35- hydroxy 11 keto 16a methylpregna 5(6),17 (2 O)-dien-21-oate for methyl 35-hydroxy-11-keto-5apregn-l7(20)-cn-2l-0ate in Example 1A above is productive of the A compounds useful as intermediates in the production of the compounds of Formula 712 and the 21-free acids otherwise corresponding to the 21-methyl ester starting material used for the preparation of the compounds of Formula 7b, namely,

35 hydroxy 16 methylpregna 5(6),l6(17) dien- 21-oic, acid and 35 hydroxy 165 methyland 35 hydroxy cmethylpregna-5(6), 17 (2O) -dien-21-oic acid,

35,115 dihydroxy 16 methylpregna 5(6),16(l7)- dien-2l-oic acid and 35,115 dihydroxy methyland 35,115 dihydroxy 16cc methylpregna 5(6),l7(20) dien 21- oic acid and 1% 35 hydroxy 11 keto 16 methylpregna 5(6),16

(17 )-dien-21-oic acid and v 35 hydroxy 11 keto 165 methyland 35 hydroxy- 11 keto 16oz methylpregna 5(6),17(20) dien- 21-oic acid, respectively.

The above described A -21-free acids are reesterified, according to procedures known in the art for the esterification of 21-free acids, such as those disclosed by Reindel and Niederlander, Ber. 688, 1969-73 (1935), to convert them back to the A -21-methyl esters and recycled for use as starting materials.

113. 313,1GIIi-DIHYDROXY-l1-KETO-17wIODO-5a-PREGNAN- 21-OIC ACID 'y-LACTONE To a solution containing 1.0 g. of 35-hydroxy-11-keto- 5a-pregn-16(17)-en-21-oic acid, 1.6 g. of potassium bicarbonate and 25 ml. of water there was added a solution containing 2.5 g. of iodine and 6.0 g. of potassium iodide in 50 ml. of water. The thus obtained reaction mixture, comprising 35,165 dihydroxy 11 keto 17a. iodo- 5a-pregnan-21-oic acid v-lactone was stirred for about minutes and then allowed to stand overnight at room temperature. The reaction mixture was extracted with methylene chloride and the methylene chloride solution was washed successively with sodium thiosulfate solution, sodium bicarbonate solution, and water, dried over sodium sulfate, and the solvent was removed leaving a crystdline residue which was triturated with methanol. Removal of the methanol yielded a crystalline material, comprising 35,165 dihydroxy 11 keto 170a iodo- 5a.-pregnan-21-oic acid 'y-lactone having a melting point of 220 C. (dec.). Recrystallization of the crystalline material from acetone-commercial hexanes yielded an analytical sample of 35,165-dihydroxy-1l-keto-lh-iodo- 5a-pregnan-21-oic acid 'y-lactone having a melting point of 223 -229 C. (dec.), infrared absorption bands (Nujol) at 354-0, 1770, 1705, 1165, 1135, and 1035 cm. and the following analysis:

Analysis.-Calcd. for C H O I: C, 53.34; H, 6.14; I, 26.9. Found: C, 54.75; H, 6.70; I, 23.72.

The substitution of bromine for iodine and potassium bromide for potassium iodide is productive of 35,165- dihydroxy 11 keto 17a. bromo 5a pregnan 21- oic acid 'y-lactone.

The substitution of chlorine for iodine and potassium chloride for potassium iodide is productive of 35,165- dihydroxy 11 keto 17cc chloro 5a pregnan 21- oic acid -lactone.

Similarly, substituting a stoichiometric equivalent amount of 3-ketopregna-4,16 17) -dien-21-oic acid,

3-ketopregna-l,4, 16 17 -trien-21-oic acid,

3-keto-1 15-hydroxypregna-4,16 17 -dien-21-oic acid,

3-keto-1 15-hydroxypregna-1,4,16(17)-tricn-21-oic acid,

3 ,11-diketopregna-4,16(17)-dien-21-oic acid,

3,11-diketopregna-1,4,16(17)-trien-21-oic acid,

3 keto 9a fluoro 115 hydroxypregna 4,16(17)- dien-21-oic acid,

3 keto 90c fluoro 115 hydroxypregna 1,4,16(17)- trien-21-oic acid,

3,1 l-diketo-9u-fiuoropregna-4,16(17)-dien-21-oic acid,

3,11-diketo-9a-flu0ropregna-1,4,l6(17)-trien-21-oic acid,

3-ketopregna-4,9(11),16(17)-trien-21-oic acid, and

3-ketopregna-1,4,9(11),16(17)-tetraen-21-oic acid for hydroxy-l1-keto-5oc-pregn-16(17)-en-21-oic acid in Example 13 above is productive of the 170z-i0dOlaCtO116S useful as intermediates in the production of the compounds of Formula 1, namely,

3 keto 165 hydroxy 17a iodopregn 4 en 21- oic acid 'y-lactone,

3 keto 165 hydroxy 17oz iodopregna 1,4 dien-21- oic acid 7 lactone,

3 keto 115,165 dihydroxy 17a iodopregn 4 en- 2l-oic acid 'y-lactone,

3 keto 115,165 dihydroxy 17a. iodopregna 1,4-

dien-Zl-oic acid -lactone,

3,11 diketo 165 hydroxy 17a iodopregn 4 en- 21-oic acid 'y-lactone,

3,11 diketo 165 hydroxy 17a iodopregna 1,4-dien- 2l-oic acid 'y-lactone,

3 keto fluoro 115,165 dihydroxy 17a iodopregn-4-en-21-oic acid 'y-lactone,

3 keto 90 fluoro 115,165 dihydroxy 17a iodopregna-1,4-dien-21-oic acid -lactone,

3,11 diketo 90c fluoro hydroxy 17a iodopregn-4-en-2l-oic acid y-lactone,

3,11 diketo 90c fluoro 165 hydroxy 17a -iodopregna-1,4-dien-21-oic acid y-lactone,

3 keto 165 hydroxy 17a iodopregna 4,9(11)- dien-Zl-oic acid y-lactone, and

3 keto 165 hydroxy 17a iodopregna 1,4,9(l1)- trien-21-oic acid 'y-lactone, respectively.

Similarly, substituting a stoichiometric equivalent amount of 2a-methyl-3-keto-115,165-dihydroxy 17a iodopregn-4- en-2l-oic acid 'y-lactone,

2u-rnethyl-3,11-diketo-165-hydroxy 17a iodopregna-4- en-21-oic acid 'y-lactone,

2a-methyl-3-keto-9a fiuoro 115,165 dihydroxy ciodopregn-4-en-21-oic acid 'y-lactone,

2a-metbyl-3,11-diketo-9a-fiuoro-165-hydroxy l7oc-i0d0- pregn-4-en-21-oic acid 'y-lactone, and

2a-rnethyl-3-keto-l65-hydroxy 17oz iodopregna-4,9( l1)- dien-21-oic acid y-lactone, respectively.

Similarly, amount of substituting a 'stoichiometric equivalent 3-keto-6a-methylpregna4,16(17)-dien-21-oic acid,

3-keto-6a-methyl-l15-hydroXypregna-4,16(17) dien 21- oic acid,

3-keto-6a-methyl-115-hydroxypregna 1,4,16(l7) trien- 2l-oic acid,

3,11-diketo-6a-metbylpregna-4,16(17) dien 21-oic acid,

3,11-diketo-6 :-methylpregna-1,4,16(17)-trien-21-oic acid,

3-keto6a-methyl 90c fiuoro-115 hydroxypregna-4,16

(17)-dien-21-oic acid,

3-keto-6a-methyl 9oc-fiu0IO 115-hydroxypregna-1,4,l6

(17)-trien-21-oic acid,

3,11-dil eto-6a-methyl-9zx-fluoropregnat,16(17) dien-21- oic acid,

3,11-dikete-6 x-methyl-9a-fiuoropregna 1,4,16(17)-trien- 2l-oic acid,

3-keto-6a-methylpregna-4,9( 11),l6(17)-trien-21-oic acid,

and

3-keto-6a-methylpregna-1,4,9(11),l6(l7) tetraen 21- oic acid for 35-l1ydroxy-11-keto-5a-pregn16(17)-en- 21-oic acid in Example 13 above is productive of the 17a-iodolactones useful as intermediates in the production of the compounds of Formula 2b, namely,

3-keto-6a-methyl-165-hydroxy-l7a-iodopregn-4-en-21- oic acid y-lactone,

3-ket0-6a-methyl-115,165-dihydroxy 17oz iodopregn-4- en-Zl-oic acid 'y-lactone,

3-keto-6oa-mcthyl-1 15, l65-dihydroxy-17a-iodopregna-1,4-

dien-Zl-oic acid 'y-lactone,

3,1 l-diketo-6a-methyl-165-hydr0xy-17oc-iodopregn-4-en- 21-oic acid 'y-lactone,

3,1 1-diketo-6a-methyl-165-l1ydroxy-17a-icdopregna-1,4-

dien-Zl-oic acid 'y-lactone,

3-keto-6ot-methyl-9a-fluoro-1 15,165-dihydroxy-17aiodopregn-4-en-21-oic acid 'y-lactone,

3-keto-6ot-methyl-9u-fluoro-115,165-dihydroxy-17miodopregna-1,4-dien-21-oic acid 'y-lactone,

3, 1 1-diketo-6a-methyl-9a-fluoro- 16 5-hydroxy-17ixiodopregn-4-en-2 l-oic acid 'y-lactone,

3-keto-6a-metl1yl-165whydroxy-17a-iodopregna-4,9 1 1 dien-Zl-oic acid 'y-lactone and 3-keto-6a-methyl-165-hydroxy-17a-iodopregna-l,4,9(11

trien-Zl-oic acid 'y-lactone, respectively.

Similarly, amount of 3-keto- 1 15-hydroxy-1 6-methylpregna-4, 16 17) -dien-21- oic acid,

3-keto-1 15-hydroxy-16-methylpregna-1,4,16( 17 --trien- 21-oic acid,

3,11-diketo16-methylpregna-4,16( 17)-dien-21-oic acid,

3,1 1-cliketo-16-methylpregna-1,4,16( 17) -ttien-21-oic acid,

3-keto-9a-fluono-1 15-hydroXy-16-methylpregna-4,16 17 dien-21-oic acid,

3-keto-9a-fluoro-1 15-hydroxy-16-methylpregna-1,4-16

( 17) -trien-21-0ic acid,

3,1 1-diketo-9a-fluoro-16-methylpregna-4,16(17) -dien-21- oic acid,

3, 1 1-diketo-9u-fluoro-16-methylpregna-L4, 16 17 -trien- 21-oic acid,

3-keto-16-methylpregna-4,9(11),16(17)trien-21-oic acid,

and

3-keto-16-methylpregna 1,4,9 1 1 ),16( 17) tetraen-Zloic acid for 35-hydroxy-1l-keto-5ot-pregn-16( 17 -en- 21-oic acid in Example 113 above is productive of the 17a-iodolactones useful as intermediates in the production of the compounds of Formula 20, namely,

3-keto-115,165-dihydr0xy-16a-methyl-17ix-iodopregn-4- en-21-oic acid 'y-lactone,

S-keto-l l 5,165-dihydroxy-l6ot-methyl-17a-iodopregna-1,

4-dien-2 l-oic acid 'y-lactone,

3,1 l-dilteto-165-hyclroxy-16a-methyl-17a-iodopregn-4-en- 21-oic acid 'y-lactone,

3,1 1-diketo-165-hydroxy-1Get-methyl-17a-iodopregna-1,4-

dien-Zl-oic acid 'y'lactone,

3-k6tO-9oc-flllOrO-l l5,165,dihydroxy-16ot-methyl-17aiodopregn-4-en-21-oic acid 'y-lactone,

3-keto-9ix-fiuoro-l 15,165-dihydroxy-16a-methyl17aiodopregna-1,4-dien21-oic acid 'y-lactone,

3,11-keto-9u-fluoro-165=hydr0xy-16a-rnethyl-17aiodopregni-en-Zl-oic acid 'y-l-actone,

3,11-diketo-9u-fiuoro-165-hydroxy-16u-methyl-17uiodopregna-1,4-dien-21-oic acid 'y-lactone,

3-keto-165-hydroxy-16ot-methyl-l7a-iodopregna-4,9 1 1)- dien-21-oic acid v-laetone and 3-keto-165-hydroxy-16ix-methyl-175-iodopregna-1,4,9

(1 1)-trien-21-o-ic acid 'y-laetone, respectively.

substituting a stoichiometric equivalent Similarly, amount of substituting a stoichiometric equivalent 22. Similarly, substituting a stoichiometric equivalent amount of 35-hydroxy-5a-pregn-16(17) -en-21-oic acid, 35,115-dil1ydroxy-5a-pregn-16(17)-en-21-oic acid, and 35,11a-dihydmXy-Saregn-16(17)-en-21-oic acid for 35-hydroxy-11-keto-5a-pregn-16(17)-en-21-oic acid in Example 1B above is productive of the 17a-i0dolactones useful as intermediates in the production of the compounds of Formula 4a, namely, 35,165-dihydroxy-17a-iodo-5u-pregnan-2 l-oic acid 'y-lactone, 35,1l5,165-trihydroxy-17a-iodo-5a-pregnan-2l-oic acid lactone, and 35,11a,165-trihydroxy-17a-iodo-5a-pregnan-2l-oic acid 7- lactone, respectively.

substituting a stoichiometric equivalent lactone, respectively.

Similarly, substituting a stoichiometric equivalent amount of 35,115 dihydroxy 16 methyl 5a pregn 16(17)- en-21-oic acid and 35 hydroxy -11- keto 16 methyl c pregn -16(17)- en 21 oic acid for 35 hydroxy 11 keto 5apregn-16(17)en-21-oic acid in Example 1B above is productive of the 17a-iodo1actones useful as intermediates in the production of the compounds of Formula 5a, namely,

35,115,165 trihydroxy 16a methyl 17cc iodo 5apregnan-Zl-oic acid -lactone and 35,165 dihydroxy 11 keto 16a methyl 17a iodo- 5a-pregnan-2l-oic acid 'y-lactone, respectively.

Similarly, amount of 3a,115 dihydroxy 16 methyl pregn 16(17)- en-21-oic acid and 30c hydroxy 11- keto 16 methyl 55 pregn -16(17)- en 21 oic acid for 35 hydroxy 11 keto 50L- pregn-16(17)-en-21-oic acid in Example 1B above is productive of the 17x-iodolact0nes useful as intermediates in the production of the compounds of Formula 5b, namely,

304,115,165 trihydroxy 16a methyl 17oz iodo 55- pregnan-Zl-oic acid 'y-lactone and 3oc,165 dihydroxy 11 keto 16a methyl 17a iodo- 55-pregnan-21-oic acid 'y-lactone, respectively.

Similarly, amount of substituting a stoichiometric equivalent tones useful as intermediates in the production of the compounds of Formula 6, namely,

35,165-dihydroxy-17a-iodopregn-5(6)-en-21-oic acid 7- lactone,

35,115,165 trihydroxy 17cc iodopregn (6) en 21- oic acid 'y-lactone,

35,165 dihydroxy 11 keto 17a iodopregn 5(6)- en-21-oic acid 'y-lactone, and

35,11a,165-trihydroxy-17a-iodopregn-5(6)-en-21-oic acid v-lactone, respectively.

Similarly, substituting a amount of 3 5-hydroxy-6-methylpregna-5 (6),16(17)-dien-2l-oic acid,

35,115 dihydroxy 6 methylpregna 5(6),16(17)- dien-21-oic acid, and

35 hydroxy 6 methyl 11- ketopregna 5(6),16(17)- dien-Zl-oic acid for 35-hydroxy-11-keto-5a-pregn- 16(17)-en-21-oic acid in Example 1B above is productive of the 17a-iodolactones useful as intermediates in the production of the compounds of Formula 7a, namely,

35,165 dihydroxy 6 methyl 17cc iodopregn 5(6)- en-21-oic acid -lactone,

35,115,165 trihydroxy 6 methyl 17a iodopregn- 5(6)-en-21-oic acid 'y-lactone, and

35,165 dihydroxy 6 methyl 11 keto 17a iodopregn-5(6)-en-21-oic acid -lactone, respectively.

stoichiometric equivalent Similarly, amount of 35 hydroxy- 16 methylpregna 5(6),16(17) dien 21- oic acid,

35,115 dihydroxy 16 methylpregna 5(6),16(17) dien-Zl-oic acid, and

35-hydroXy 11 keto 16 methylpregna 5(6),16(l7)- dien-21-oic acid for 35-hydroxy-11 keto Sa-pregn-IG(17)-en-21-oic acid in Example 18 above is productive of the 17a-iodolactones useful as intermediates in the production of the compounds of Formula 7b, namely,

35,165 dihydroxy 16a methyl 17cc iodopregn- 5(6)-en-21-oic acid -lactone,

35,115,165 trihydroxy 160a methyl 17o: iodopregn- 5(6)-en-2l-oic acid 'y-lactone, and

35,165 dihydroxy 11 keto 16oz methyl 17a iodopregn-5(6)-en-21-oic acid 'y-lactone, respectively.

substituting a stoichiometric equivalent The substitution of bromine or chlorine for iodine and potassium bromide or potassium chloride for potassium iodide with the appropriate starting materials named following Example 113 is productive of the corresponding 17a-bromolactone or 17a-chlorolactone, respectively, e.g.,

3 keto 165 hydroxy 17a bromopregn 4 en 21 oic acid 'y-lactone,

3 keto 165 hydroxy 17a chloropregn 4 en 2 oic acid 'y-lactone and 3 keto 60c methyl 115,165 dihydroxy 17oz bromopregn-4-en-21-oic acid 'y-lactone and 3 keto 6a methyl 115,165 dihydroxy 17a chloropregn-4en-21-oic acid 'y-lactone.

14.85 g. of 35,165-dihydroXy-11-keto-17a-iodo-5a-pregnan-21-oic acid y-lactone dissolved in 50 ml. of pyridine was stirred at room temperature for approximately 3 days. The reaction mixture, comprising 35,165-dihydroxy-11- keto-5a-pregn-17(20)-en-21-oic acid 'y-lactone, was diluted with methylene chloride and washed successively with dilute hydrochloric acid, sodium bicarbonate solution, and water, and dried over sodium sulfate. Removal of the solvent yielded a crystalline residue which was recrystallized from acetone-commercial hexanes to yield a first crop (8.5 g., melting point 259264 C.) and a second 24- crop (0.90 g., melting point 260-265" C.) of crystals comprising 3 5,165-dihydroxy-1 1-keto-5a-pregn-17(20) -en-21- oic acid 'y-lactone. The two crops were combined and recrystallized from acetone-commercial hexanes to yield 35,165-dihydroxy 11 keto-5a-pregn-17(20)-en-21-oic acid -lactone having a melting point of 259-264 C.,

ELOH max.

216 my, a 13,300,

infrared absorption bands (Nujol) at 3460, 1780, 1733, 1700, 1640, 1165, 1125, 1080, 1040, 1015 cmr and the following analysis:

Analysis.Calcd .for C H O C, 73.22; H, 8.19. Found: C, 73.02; H, 8.20.

Substituting 35,165-dihydroxy-11-keto-17a-bromo-5apregnan-Zl-oic acid 'y-lactone or 35,165-dihydroxy-11- keto-17ot-chloro-5a-pregnan-2l-oic acid 'y-lactone for 35, -dihydroXy-1l-keto-17ot-iodo-5a-pregnan-2l-oic acid 'y-lactone is productive of 35,165-dihydroxy-1l-keto-Sapregn-17 (20)-en-21-oic acid 'y-lactone.

Similarly, substituting a stoichiometric equivalent amount of 3-keto-165hydroxy-17a-iodopregn-4-en-2l-oic acid 7- lactone,

3-keto-16-hydroxy-17a-iodopregna-1,4-dien-21-oic acid 7- lactone,

3-keto-1 1 5,165-dihydroXy-17 a-iodopregn-4-en-21-oic acid 'y-lactone,

3-keto-l15,165-dihydroxy-17a-iodogregna-1,4-dien-21-oic acid 7-lact0ne,

3,1 1-diketo-165-hydroxy-17a-iodopregn-4-en-2l-oic 'y-lactone,

3,1 1-diketo-165-hydroXy-17a-iodopregna-1,4-dien-21-oic acid 'y-lactone,

3-keto-9a-fiuoro-115,165-dihydroxy-17a-iodopregn-4-en- 21-oic acid 'y-lactone,

3-keto-9u-fluoro-1 15,165-dihydroxy-17a-iodopregna-l,4-

dien-21-oic acid 'y-lactone,

3,1 1-diketo-9ot fluoro-165-hydroxy-l7a-iodopregn-4-en- 21-oic acid y-lactone,

3,11-diketo-9a-fiuor0-165-hydroxy-17a-iodopregna-1,4-

dien-2l-oic acid q-lactone,

3-keto-165-hydroxy-17a-iodopregna-4,9(1 1 )-dien-21-oic acid 'y-lactone, and

3-keto-165-hydroxy-17a-iodopregna-1,4,9 1 1 -trien-21- oic acid 'y-lactone, for

acid

35,165 dihydroXy-11-keto17a iodo pregnan-21-oic acid 'y-lactons in Example 1C above is productive of the compounds of Formula 1, namely,

27 3 5, 1 10a, 1 65-trihydroxy-5 a-pregn- 17 (20) -en-2 l-oic acid 7- lactone, respectively.

Similarly, substituting a stoichiometric equivalent amount of 3a,165-dihydroxy-17ot-iodo-55-pregnan-21-oic acid 'y-lactone,

30:,1 15,165-trihydroxy-17a-iodo-55-pregnan-21-oic acid -lactone,

3 a,165-dihydroxy-11-keto-17a-iodo-55-pregnan-21-oic acid 'y-lactone, and

35,165-dihydroxy-1 l-ketO-l7oc-iOdO-50c-P1'6gl'l2t11-2l-QiC acid 'y-lactone in Example 1C above is productive of the compounds of Formula 4b wherein R is hydrogen, namely,

3 a,165-dihydroxy-55-pregn-17(20)-en-21-oic acid 'y-lactone,

311,115,165-trihydroxy-S5-pregn-17(20)-en-21-oic acid 'y-lactone,

3 a, l 65-dihydroxy-l 1-keto-55-pregn-1 7 (20 -en-2 l-oic acid 'y-lactone, and

3oc,1 1a,165-trihydroxy-55-pregn-17 (20) -en-2l-oic acid 'y-lactone, respectively.

Similarly, substituting a stoichiometric equivalent amount of 35,115,165-trihydroxy-16a-methyl-17oc-iodo-5apregnan-Zl-oic acid y-lactone and 35,165-dihydroxy-1l-keto-l6a-methyl-17tx-iodo-5apregnan-Zl-oic acid 'y-lactone for 35,165-dihydroxy- 1l-keto-l7ot-iodo-5a-pregnan-2l-acid v-lactone in Example 1C above is productive of the compounds of Formula 5a wherein R is hydrogen, namely,

35,1l5,165-trihydroxy-l6a-methyl-5a-pregn-17(20)- en-21-oic acid 'y-lactone and 35,165-dihydroxy-l1-keto-16a-methyl-5a-pregn-17(20)- en-21-oic acid y-lactone, respectively.

Similarly, substituting a stoichiometric equivalent amount of 30:,1 15,l65-trihydroxy-16m-methyl-17a-iodo-55- pregnan-Zl-oic acid -lactone and 3a,165-dihydroxy-l l-keto-l 6tx-methyll 7a-iodo-55- pregnan-Zl-oic acid 'y-lactone for 35,165-dihydroxy- 1l-keto-l7a-iodo-5a-pregnan-2l-oic acid v-lactone in Example 1C above is productive of the compounds of Formula 5b wherein R is hydrogen, namely,

3 a,1 15,165-trihydroxy-16a-methyl-55-pregn-17(20)- en-21-oic acid ql-lactone and 3 a,165-dihydroxy-ll-keto-l6a-methyl-55-pregn-17(20) en-21-oic acid 'y-lactone, respectively.

Similarly, amount of 35,165-dihydroxy-17u-iod0pregn-5 (6) -en-21-oic acid 'y-lactone,

35,115,165-trihydroxy-l7ot-iodopregn-S (6 -en-2 l-oic acid y-lactone,

35,165-dihydroxy-1 1-keto-l7ct-iodopregn-5 (6 -en-2 1- oic acid 'y-lactone, and

35,1 1a,165-trihydroxy-17a-iodopregn-5 (6)-en-21-oic acid 7 lactone for 35,165 dihydroxy 11 keto 17aiodo-5a-pregnan-2l-oic acid 'y-lactone in Example lC above is productive of the compounds of Formula 6 wherein R is hydrogen, namely,

substituting a stoichiometric equivalent 3 5, l 6 5-dihydroxypregna-5 6 l 7 (20 -dien-2 l-oic acid 'y-lactOne,

35, 1 l 5,165-trihydroxypregna-5 (6) 17 (2O -dien-21-oic acid 'y-lactone,

3 5,165-dihydroxy-1 1-ketopregna-5(6) 17 20)-dien-21- oic acid 'y-lactone, and

35,11a,165-trihydroxypregna-5 (6),17 (20) -dien-21-oic acid 'y-lactone, respectively.

28 Similarly, substituting a stoichiometric equivalent amount of 35,165-dihydroxy-6-methyl-l7a-iodopregn-5 (6 -en- 21-oic acid 'y-lactone,

35,1 15,165-trihydroxy-6-rnethyl-l7u-iodopregn-5 (6 en-21 oic acid 'y-lactone, and

35,165-dihydroxy-6-methyl-1 1-keto-17a-iodopregn- 5 (6)-en-21-oic acid 'y-lactone for 35,165-dihydroxy-11-keto-17m-iodo-5u-pregnan-2l-oic acid 'y-lactone in Example 1C above is productive of the compounds of Formula 7a wherein R is hydrogen, namely,

3 5, l 65-dihydroxy-6-methylpre gna-S (6 17 (20) -dien- 2l-oic acid 'y-lactone,

35,115,165-trihydroxy-6-methylpregna-5(6),17(20)- dien-21-oic acid *y-lactone, and

35,165-dihydroxy-6-methyl-11-ketopregna-5(6),17(20)- dien-Zl-oic acid 'y-lactone, respectively.

Similarly, substituting a stoichiometric equivalent amount of 35,165-dihydroxy-16a-methyl-17a-iodopregn-5 (6)- en-21-oic acid 'y-lactone, 35,115,165-trihydroxy-16a-methyl-17a-iodopregn-5(6)- en-21-oic acid 'y-lactone and 35,165-dihydroxy-l l-keto-l 6a-methyl-17a-iodopregn- 5(6)-en-21-oic acid 'y-lactone for 35,165-dihydroxy-1 l-ketol7a-iodo-5 a-pregnan-21-oic acid v-lactone in Example 1C above is productive of the compounds of Formula 7b wherein R is hydrogen, namely, 35,165-dihydroxy-1Ga-methyIpregna-S (6) ,17(20)- dien-Zl-oic acid 'y-lactone, 35,115,165-trihydroxy-16a-rnethylpregna-5(6),l7(20)- dien-21-oic acid *y-lactone, and 35,165-dihydroxy-1l-keto-16a-rncthylpregna-5 (6) l7(20)-dien-2l-oic acid y-lactone, respectively.

Substituting the corresponding 17u-bromolactones or l7oc-Chl0f0l21CtOnBS for the 17x-iodolactones named above is productive of the respective A lactones named above. Thus, for example, the substitution of 3-keto-165-hydroxy-17a-bromopregn-4-en-21-oic acid 'y-lactone or S-keto-165-hydroxy-17a-chloropregn-4- en-21-oic acid y-lactone for 3-keto-165-hydroxy-17aiodopregn-4-en-21-oic acid v-lactone is productive of 3-keto-165-hydroxypregna-4, 17 (20) -dien-2l-oic acid 'y-lactone and the substitution of 3-keto-6amethyl-1 15,165-dihydroxy-17u-bromopregn-4-en-21- oic acid y-lactone or 3 -ket0-6u-methyl-1 15,165-dihydroxy-17a-chloropregn- 4-en-21-oic acid 'y-lactone for 3-keto-6u-methyl-1 15,165-dihydroxy-17a-iodopregn- 4-en-21-oic acid 'y-lactone is productive of 3-keto-6amethyl-115,165-dihydroxypregna-4,17(20)-dien-21- oic acid 'y-lactone.

1D. 3fl-ACETOXY-1Gfl-HYDROXY-l1-KETO-5a-PREGN- 17(20)-EN-21-OIC ACID 7-LACTONE A mixture of 1 g. of 35,165-dihydroxy-1l-keto-Sapregn-17(20)-en-21-oic acid 'y-lactone, 2 ml. of acetic anhydride and ml. of pyridine was stirred and then allowed to stand at room temperature for approximately 18 hours. The reaction mixture was then poured into ice:water and the crystalline material comprising 35-acetoxy-l 65-hydroxy-1 1-keto-5a-pregn-l7 (20) -en-2l-oic acid 'y-lactone which had formed was removed by filtration, washed with water and dried in vacuo. The crystalline material was then recrystallized from acetone:commercial hexanes to give 0.63 g. of product comprising 35-acetoxy- -hydroxy-lI-ketQ-Su-pregn 17(20) en 21 oic acid 'y-lactone having a melting point of 235240 C. Two further recrystallizations from acetonezcommercial hexanes yielded 35-acetoxy-165-hydroxy-1l-keto-5a-pregn- 17 (20)-en-21-0ic acid 'y-lactone having a melting point 29 of 255258 C., infrared absorption bands (Nujol) at 1780, 1735, 1710, 1645, 1240, 1160, 1020, and 1010 cm." and an ultraviolet analysis of xii-3F 217 m 6 14,350 and the following analysis:

Analysis.--Calcd. for (1 1-1 C, 71.43; H, 7.82. Found: C, 71.43; H, 7.94.

Similarly, by reacting the appropriate hydrocarbon carboxylic acid anhydride such as these given in the penultimate paragraph of the body of the disclosure, with 35,165-dihydroxy-11-l eto-5u-pregn-l7(20)-en-21-oic acid 'y-lactone, is productive of other 3-acyloxy derivatives.

Similarly, reacting 35,165 dihydroxy-5a-pregn-17(20)-en-21-oic acid 'y-lactone,

35,115,165-trihydroxy-5ix-pregn-17(20)-en 21 oic acid 'y-lactone, and

35,11a,165-trihydroxy-5u-pregn-17(20)-en 21 oic acid 'y-lactone With acetic anhydride (or With other hydrocarbon carboxylic anhydrides, such as those given in the penultimate paragraph of the body of the disclosure), according to the procedure of Example 1D, is productive of the corresponding 3-esters of the compounds of Formula 40, namely,

35 acetoxy (acyloxy)-165-hydroxy-5a-pregn-17(20)-en- 21-0ic acid *y-lactone,

35 acetoxy (acyloxy) 115,165 dihydroxy 50c pregn- 17(20)en-21-oic acid 'y-lactone, and

35,11a-diacetoxy (diacyloxy) 165 hydroxy 5a pregn- 17(20)-en-2l-oic acid 'y-lactone, respectively.

Similarly, reacting 3a,165-dihydroxy-55-pregn-17(20)-en-21-oic acid y-lactone,

311,115,165-trihydroxy-55-pregn-17 (20) en 21 oic acid 'y-lactone,

3u,165-dihydroxy-l1-keto-55-pregn-17(20)-en-21-oic acid 'y-lactone, and

304,11a,165-trihydroxy-55-pregn-17(20)-en 21 oic acid 'y-lactone with acetic anhydride (or with other hydrocarbon carboxylic anhydrides, such as those given in the penultimate paragraph of the body of the disclosure), according to the procedure of Example 1D, is productive of the corresponding 3-esters of the compounds of Formula 4b, namely,

Ba-acetoxy (acyloxy)-165-hydroxy-55-pregn- 17(20)-en- 21-oic acid 'y-lactone,

3m acetoxy (acyloxy) 115,165 dihydroxy 5 5 pregn- 17(20)-en-21-oic acid 'y-lactone,

3a-acetoxy (acyloxy)-165-hydroxy-11 keto 5 5 pregn- 17(20)-en-21-oic acid 'y-lactone, and

3a,11x-diacetoxy (diacyloxy)-165 hydroxy '5 5 pregn- 17(20)-en-21-oic acid 'y-lactone, respectively.

Similarly, reacting 35,115,165-trihydroxy-16u-methyl-5a pregn 17(20)-en- 21-oic acid 'y-lactone, and

35,165-dihydroxy-1 1-k6t0-160c-II16111Y1 5a pregn-17(20)- en-21-oic acid 'y-lactone with acetic anhydride (or with other hydrocarbon carboxylic anhydrides, such as those given in the penultimate paragraph of the body of the disclosure), according to the procedure of Example ID, is productive of the corresponding 3-esters of the compounds of Formula 5a, namely,

35-acetoxy (acyloxy)-115,165-dihydroxy-16a-methyl 5ozpregn-17(20)-en-21-oic acid 'y-lactone, and

35-acetoxy (acyloxy)-165-hydroxy-11-keto-16a methyl- 5ot-pregn-17(20)-en-21-oic acid 'y-lactone, respectively. Similarly, reacting 35,115,165-trihydroxy-16a-methyl-55-pregn 17(20) en- 21-oic acid -lactone and 3 5,165-dihydroxy-1 1-keto-16a-methyl-5 5 pregn 17(20)- en-21-oic acid 'y-lactone With acetic anhydride (or with other hydrocarbon carboxylic anhydrides, such as those given in the penultimate paragraph of the body of the disclosure), according to the procedure of Example 1D, is productive of the corresponding 3-esters of the compounds of Formula 5 b, namely,

35-acetoxy (acyloxy)-115,165-dihydroxy 16oz methyl- 55-pregn-17(20)-en-21-oic acid 'y-lactone and 35-a-cetoxy (acyloxy)--hydroxy-11-keto-16u methyl- 55-pregn-l7(20)-en-21-oic acid 'y-lactone, respectively.

Similarly, reacting 35-165-dihydroxypregna-5(6),17(20) dien 21 oic acid -lactone,

35-115-165-trihydroxypregna5(6),17(20) dien 21 oic acid y-lactone,

35-165-dihydroxy-11- xetopregr1a-5(6),17(20) dien 21- oic acid 'y-lactone, and

35-11a,165-trihydroxypregna-5(6),17(20) dien 21 oic acid 'y-lactone with acetic anhydride (or with other hydrocarbon carboxylic anhydrides, such as those given in the penultimate paragraph of the body of the disclosure), according to the procedure of Example 1D, is productive of the corresponding 3-esters of the compounds of Formula 6, namely,

35-acetoxy (acyloxy) 165 hydroxypregna-S (6),17(20)- dien-Zl-oic acid 'y-lactone,

35-hydroxy (acy1oxy)-115 165 dihydroxypregna 5(6),

17(20)-dien-21-oic acid 'y-lactone,

35 acetoxy (acyloxy)-165-hydroxy-1 l-ketopregna-S (6),

17(2())-dien-2l-0ic acid 'y-lactone, and

35-l1oz-diacetoxy (diacyloxy)-165-hydroxypregna 5(6),

17(20)-dien21-oic acid -lactone, respectively.

Similarly, reacting 35-165-dihydroxy 6 methylpregna 5(6),17(20)-dien- 21-oic acid 'y-lactone,

35,115,165 trihydroxy 6 methylpregna 5(6),17(20)- dien-21-oic acid 'y-lactone, and

35-165-dihydroxy-6-methyl-1l-ketopregna 5 (6),17(20)- dien-Zl-oic acid 'y-lactone.

with acetic anhydride (or with other hydrocarbon carboxylic anhydrides, such as those given in the penultimate paragraph of the body of the disclosure), according to the procedure of Example 1D, is productive of the corresponding 3-esters of the compounds of Formula 7a, namely,

35 acetoxy (acyloxy) 165 hydroxy 6 methylpregna- 5 (6),17(20)-dien-21-oic acid y-lactone,

35 acetoxy (acyloxy) 115,165 dihydroxy 6 methylpregna-5(6),17(20)-dien-21-oic acid 'y-lactone, and

35-acetoxy (acyloxy)-165-hydroxy 6 methyl 11 ketopregna-Sfi),17(20)-dien-21-oic acid 'y-lactone, respecive y.

Similarly, reacting 35, 1 65-dihydroxy-1 6a-methylpregna-5 (6) 17 (20) dien-21-oic acid 'y-lactone,

35,115,165-trihydroxy-16a-methy1pregna-5(6),17(20)- dien-Zl-oic acid -lactone,

35,165-dihydroxy-1 l-keto- 1 6a-methylpregna-5 (6),

17(20)-dien-2l-oic acid v-lactone with acetic anhydride (or With other hydrocarbon carboxylic anhydrides, such as those given in the penultimate paragraph of the body of the disclosure), according to the procedure of Example 1D, is productive of the corresponding 3-esters of the compounds of Formula 7!), namely,

3 5-acetoxy (acyloxy 165-hydroxy- 1 6a-methylpregna- 5(6),17(20)-dien-21-oic acid 'y-lactone,

3 5-acetoxy (acyloxy) -l l5,165-dihydroxy-16a-methylp-regna-5(6),17(20)-dien-21-oic acid 'y-lactone, and

35 acetoxy (acyloxy)-l65-hydroXy-11-kcto-16a-methyl- 31 pregna (6 17 -dien-2 l-oic acid -lactone, respectively.

EXAMPLE 2 3,1l-D1'ket0-16fi-Hydr0xypregiza-1,4,1 7(20 Trim-21 -Oic Acid *y-Lactone 2A. 3,11-DIKETOPREGNA-1,4,16(17)-TRIEN-21-OIC ACID A suspension of 29.6 g. of methyl 3,11-diketopregna- 1,4,17(20)-trien-21-oate in 500 ml. of methanol and a solution of 30.0 g. of potassium hydroxide in 100 ml. of water was refluxed under nitrogen for about 3 hours. Following reflux most of the methanol was removed in vacuo from the reaction mixture, comprising 3,11-diketopregna-1,4-,l6(l7)-trien-2l-oic acid, leaving a residual brown solution which was boiled with approximately 2.0 g. of activated charcoal (Darco G), filtered through diatomaceous earth (Celite) and extracted with methylene chloride. The aqueous layer remaining, following the methylene chloride extraction, was acidified and extracted with several portions of ethyl acetate. acetate extracts were combined, washed with water and with two 500 ml. portions of saturated sodium bicarbonate solution. The sodium bicarbonate solutions comprising 3,11-diketopregna-1,4,16(l7)-trien 21 oic acid were used without further treatment in part 23.

DIEN-2l-OIC ACID 'y-LACTONE The sodium bicarbonate solutions obtained in part 2A were combined and added to a solution of 29.6 g. of iodine and 40.0 g. of potassium iodide in 500 ml. of water. The reaction mixture was allowed to stand for approximatcly 18 hours at about room temperature, followed by extraction with ethyl acetatezrnethylene chloride (1:1). The organic extract, comprising 3,11-diketo-16B-hydroxy- 17a-io'dopregna 1,4 dien 21 oic acid 7 lactone, was washed successively with sodium thiosulfate solution, saturated aqueous sodium bicarbonate, and water, and dried over sodium sulfate. The solvent was then removed from the dried solution leaving a residue which was triturated with ether-methanol. Removal of the ether-methanol yielded 2.4 g. of crystalline material comprising 3,11- diketo-l6B-hydroxy-17a-iodopregna- 1,4 dien 21 oic acid 'y-lactone and having a melting point of 205 C. (dec.).

2C. 3,11-DIKETO-1Gfl-HYDROXYPREGNA-IA,17(20)- TRIEN-21-OIC ACID 'y-LACTONE 2.0 g. of the crystalline material comprising 3,11-diketo-l6B-hydroxy-17a-iodopregna-1,4-dien 21 oic acid 'y-lactone, obtained in part 23, suspended in 20 ml. of pyridine was stirred for approximately 3 days at about room temperature. The reaction mixture, comprising 3, 1l-diketo-l6fi-hydroxypregna-1,4,17(20)-trien 21 oic acid v-lactone, was diluted with water and extracted with several portions of methylene chloride. The methylene chloride extracts were combined, washed successively with ice cold dilute hydrochloric acid, sodium bicarbonate solution and water, and dried over sodium sulfate. The oil obtained upon removal of the solvent was dissolved in 20 ml. of methylene chloride and poured onto a chromatographic column containing 100 g. of Florisil (synthetic magnesium silicate) packed wet in commercial hexanes. The chromatographic column was developed by eluting with commercial hexanes containing increasing amounts of acetone. The eluate fractions were freed of solvent and those fractions which infrared analysis and paper chromatography showed to contain the desired product, namely, those fractions eluted with 25-40 percent acetonez75-60 percent commercial hexanes, were combined and recrystallized from methanol to give a first crop (0.45 g.) and a second crop (0.34 g.) of crystals comprising 3,11 diketo-166-hydroxypregna-1,4,17(20)- trien-21-oic acid 'y-lactone, both crops having a melting point of 216219 C. The first crop (0.47 g.) was recrystallized from acetone-commercial hexanes to yield an The ethyl I a e ara analytical sample of 3,1l-diketo-lofl-hydroxypregnw1,4, 17(20)trien-21-oic acid 'y-lactone having a melting point of 218-220 C.,

max.

EXAMPLE 3 3,11-Diket0-]6/3-Hydr0xypregna-4J 7 (20) -Dien- 21-Oic Acid 'yLact0ne 3A. 3,11-DIKETO-1Gfl-HYDROXY-17aIODOPBEGN-4EN- 21 OIC ACID 'y-LACTONE A solution containing 45.5 g. of 3,11-diketopregna- 4,16(17)-dien-21-oic acid in aqueous potassium bicarbonate (30 g. of potassium bicarbonate in 1200 ml. of water) was added with stirring to a solution of g. of iodine and 300 g. of potassium iodide in 2400 ml. of water. The reaction mixture, comprising 3,11-diketo-l6i3- hydroxy-l7a-iodopregn-4-en-2l-oic acid -lactone, was allowed to stand at about room temperature for approximately 4.5 hours and then extracted with several portions of ethyl acetate. The combined ethyl acetate extracts were washed successively with sodium thiosulfate solution, sodium bicarbonate solution, and water, and dried over sodium sulfate. The solvent was then removed to give a residue which was crystallized from acetone-commercial hexanes to yield a first crop of crystals weighing 30.5 g. and having a melting point of 195-205 C. (dec.) and a second crop of crystals weighing 3.5 g. The first and second crops were combined. A sample of the iodolactone which was recrystallized from acetone-commercial hexanes gave an analytical sample of 3,11-diketo-16f3- hydroxy-l7a-iodopregna-4-en-2l-oic acid 'y-lactone having a melting point of 218221 C. (dec.),

E1011 Mm.

A solution of 34.0 g. of 3,1l-diketo-l6fl-hydroxy-17aiodopregn-4-en-21-oic acid 'y-lactone in 200 ml. of pyridine was stirred at about room temperature for approximately 60 hours. The reaction mixture, comprising 3,11- diketo hydroxypregna-4,17(20)-dien-21-oic acid ylactone, was extracted with methylene chloride and the methylene chloride extract was washed successively with water, dilute hydrochloric acid, sodium bicarbonate solution, again with water, and dried over sodium sulfate. The crystalline residue remaining upon removal of the solvent was dissolved in methylene chloride and poured onto a chromatographic column containing 1500 g. of Florisil (synthetic magnesium silicate) packed wet in commercial hexanes. The chromatographic column was developed by eluting with commercial hexanes containing increasing amounts of acetone. The eluate fractions were freed of solvent and those fractions which infrared analysis and paper chromatography showed to contain the desired product, namely, those eluted with the 50 percent acetone-50 percent commercial hexanes, were combined and recrystallized from acetone-commercial hexanes to give a first crop (14.7 g., melting point 235238 C.) and a second crop (3.95 g., melting point 228233 C.) of crystals comprising 3,11-diketo 165 hydroxypregna-4, 17(20)-dien-21-oic acid 'y-lactone. An analytical sample of 3,1l-diketo-l6fl hydroXypregna-4,l7(20)-dien-21-oic acid 'y-lactone had a melting point of 229-236 C.,

infrared absorption bands (Nujol) at 1770, 1753, 1743, 1697, 1663, 1635, 1605, 1247, 1233, 1175,1163, 1133, and 1085 cmr and the following analysis:

Analysis.--Ca1cd. for C H O C, 74.09; H, 7.11. Found: C, 73.96; H, 7.30.

I claim:

1. A compound of the formula:

wherein the 1,2-carbon atom linkage is selected from the group consisting of single and double bond linkages, Y is selected from the group consisting of methylene CH and carbonyl %O), Z is selected from the group consisting of hydrogen and fluorine, and Y and Z can together constitute a 9(11)-double bond.

2. A compound selected from the group consisting of compounds of the following formulae:

wherein the 1,2-carbon atom linkage is selected from the group consisting of 'single and double bond linkages, X is selected from the group consisting of ,B-hydroxymethylene and carbonyl C=O), and Z is selected from the group consisting of hydrogen and fluorine, and X and Z can together constitute a 9(11)-double bond.

3. A compound of the formula:

wherein the 1,2-carbon atom linkage is selected from the linkages consisting of single and double bond linkages.

4. A compound selected. from the group consisting of compounds of the following formulae:

| l, 7 l W and wherein R is selected from the group consisting of hydrogen and the acyl radical of a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms, inclusive, and W is selected from the group consisting of methylene CH fi-hydroxymethylene carbonyl C-O and u-hydrokymethylene and a-acyloxymethylene ORz R being the acyl radical of a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms, inclusive, provided that R is the same as R when R is an acyl radical. 5. A compound selected from the group consisting of compounds of the following formulae:

and i a .wherein R isselected from the group consisting of hydrogen and the acyl radical of a hydrocarbon carboxylic ,acid containing from 1 to 12 carbon atoms, inclusive, and

X is selected from the group consisting of B-hydroxymethylene I OH and carbonyl C=O) i '0" t \O 6. A compound of the formula:

wherein R is selected from. the2group consisting of hydrogen andthe acyl radicalof ahydrocarbon carboxylic acid containing from Ito 12carbon atoms,.inclusive,.and W is selected fromthegrloup consisting of methylene CH B-hydroxyrnethylene carbonyl C=O) and a-hydroxymethylene and a-acyloxymethylene R beingthe acyl radical of a hydrocarbon carboxylic acid containing from 1 to..12 carbon-atoms, inclusive, provided that R is the same as R when R is an acyl radical. a

7. A compound selected from the group consisting of compounds of the following formulae:

wherein R is selected from the=group.consisting of hydrogen and the acyl radical of a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms, inclusive, and

Y is selected from the group consisting of methylene CH fi-hydroxymethylene H 0 and carbonyl. C=O).

8. 3,11 diketo 16/3 hydroxypregna 1,4,17(20)- trien-21-oic acid -lactone. I a l.

9. 3,11 diketo 16B hydroxypregna 4,17(20)-dien- 21-oic acid y-lactone. V

10. 3 keto 16p hydroxypregna 1,4,17(20)-trien- 21-oic acid 'y-lactone. 7

11. 3 keto- 165 hydroxypregna-4,17(20)-dien-2l- 'oic acid 'y-lactone. 1 A H 12. 3,11 diketo 90c fluoro-16fl-hydroxypregna-4,17 (20)-dien-21-0ic acid 'y-lactone.

13. 3-kCtO-9oc-flll010 11B,16fl.- dihydroxypregna-4,17 (20)-dien-21-oic acid -1actone.-

14. 3-keto-6a-methyl 16B hydroxypregna-4,17(20)- dien-21-oic acid y-lactone. r '75 .15. 3,1l-diketo-6a-methy1 16 3 hydroxypregna-4,17 (20)-dien-21-oic acid y-lactone. I

16. 3-keto-6a methyl 9a fiuoro-11B,16f3-dihydroxypregna-4,17(20)-dien-21-oic acid 'y-lactone.

17. 3-ket o-1la, l6fi-dihydroxypregna 4,17(20) 'dien- 21-oic acid 'y-lactone. V

18. 33,16,8-dihydro'xy 11 keto-5a-pregn-17(20)-en- 21-oic acid 'y-lactoneQ I 19. 3a,16 8-dihydroxy 11 keto-5B-pregn-17(20)-en- 21-oic acid 'y-lactone. V v i 20. 318,165-dihydroxy 5a pregn-17(20)-en-21-oic acid -lactone.

21. 3a,16fl dihydroxy-Sfl-pregn 17(20) en-21-oic acid -lactone.

22. 3,3,16/3-dihydroxy 11 ketopregna-5(6),17(20)- dien-21-oic acid 'y-lactone.

23. 35,165 dihydroxypregna-S(6),17(20)-dien-21-oic acid y-lactOnB. I z

24. 3,8,16/8-dihydroxy 6 methylpregna-5(6),17(20)- dien-21-oic acid q-laotone.

25. 313,165 dihydroxy-16a-methylpregna-5(6),17(20)- dien-21-oic acid -lactone.

26. A compound of the formula:

and carbonyl C =:O), Z is selected from the group consisting of hydrogen and fluorine, and Y and Z can to gether constitute a 9('ll)-double bond. I

27. A compound selected from the group consisting of compounds of tha following formulae:

37 wherein the 1,2-cai'bon atom linkage is selected from the group consisting of single bond and double bond linkages, V is selected from the group consisting of iodine, bromine, and chlorine, X is selected from the group consisting of ,B-hydroxymethylene and carbonyl C=O), and Z is selected from the group consisting of hydrogen and fluorine, and X and Z can together constitute a 9(11)-double bond.

28. A compound of the formula:

wherein the 1,2-carbon atom linkage is selected from the linkages consisting of single and double bond linkages and V is selected from the group consisting of iodine, bromine and chlorine.

29. A compound selected from the group consisting of compounds of the following: formulae:

and

wherein V is selected from the group consisting of iodine, bromine and chlorine, and W is selected from the group consisting of methylene CH fi-hydroxymethylene carbonyl C=O), and a-hydroxymethylene 30. A compound selected from the group consisting of compounds of the following formulae:

and

38 wherein V is selected from the group consisting of iodine, bromine, and chlorine, and X is selected from the group consisting of fi-hydroxymethylene and carbonyl C=O),

31. A compound of the formula:

wherein V is selected from the group consisting of iodine, bromine and chlorine, and W is selected from the group consisting of methylene CH fi-hydroxymethylene carbonyl C=O) and ot-hydroxymethylene 32. A compound selected from the group consisting of compounds of the following formulae:

m mpg H0313 wherein V is selected from the group consisting of iodine, bromine and chlorine, and Y is selected from the group consisting of methylene CH fi-hydroxymethylene wherein R is selected from the group consisting'of hydrogen and methyl, with a halogen selected from the group consisting of iodine, bromine and chlorine in an alkaline aqueous "medium to obtain a 17a-hal0lactone steroid of the pregnane series having in Ring D the structure wherein R is defined as above.

38. The process of claim 37 in which (A) the halogen is iodine ,(B) the dehydrohalogenating agent is pyridine.

'40 39. Process for the production of 16/3-hydroXy-21-carboxylic acid 'y-lactones which comprises reacting a steroid of the pregnane series having in Ring D the structure wherein R is selected from the group consisting of hy- 15 drogen and methyl, and V is selected from the group consisting of iodine, bromine and chlorine, with a tertiary amine to obtain a steroid of the pregnane series having in Ring D the structure wherein R is defined as above. 3 40. The process of claim 39 in which V is iodine and the tertiary amine is pyridine.

References Cited in the file of this patent UNITED STATES PATENTS 35 Kurath et al July 17, 1962 

1. A COMPOUND OF THE FORMULA: 